PUFA Metabolism in the Brain

**13**

**Chapter 2**

Brain Cells

*Corinne Joffre*

**Abstract**

in brain cells.

**1. Introduction**

Polyunsaturated Fatty Acid

Metabolism in the Brain and

Dietary polyunsaturated fatty acids (PUFAs) have gained more importance these last decades since they regulate the level of long-chain PUFAs (LC-PUFAs) in all cells and especially in brain cells. Because LC-PUFAs, especially those of the n-3 family, display both anti-inflammatory and pro-resolution properties, they play an essential role in neuroinflammation. Neuroinflammation is a hallmark of neurological disorders and requires to be tightly controlled or at least limited otherwise it can have functional consequences and negatively impact the quality of life and well-being of patients. LC-PUFAs exert these beneficial properties in part through the synthesis of specialized pro-resolving mediators (SPMs) that are involved in the resolution of inflammation and to the return of homeostasis. SPMs are promising relevant candidates to resolve brain inflammation and to contribute to neuroprotective functions and lead to novel therapeutics for brain inflammatory diseases. Here we present an overview of the origin and accumulation of PUFAs in the brain and brain cells and their conversion into SPMs that are involved in neuroinflammation and how nutrition induces variations in LC-PUFA and SPM levels in the brain and

**Keywords:** long-chain polyunsaturated fatty acids (LC-PUFAs), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), specialized pro-resolving mediators

Polyunsaturated fatty acids (PUFA) are essential fatty acids including precursors and long-chain PUFAs (LC-PUFAs). Precursors have to be provided by the diet because they cannot be produced by mammals [1]. They can be converted into LC-PUFAs. However, as the conversion rate is very low in human [2, 3], it is recommended to consume also LC-PUFAs that modulate LC-PUFA composition of brain and brain cells. Altered dietary intake and/or PUFA metabolism has been reported to be involved in a number of neurological disorders *via* sustained neuroinflammatory processes [4]. Indeed, LC-PUFAs are key regulators of inflammation [5]. LC-PUFAs can be metabolized into specific derivatives such as specialized proresolving mediators (SPMs) that have anti-inflammatory and pro-resolving properties [6–9], giving the LC-PUFAs and their biological derivatives a growing interest to treat inflammation and more specifically neuroinflammation. Hence, they may

(SPMs), nutrition, neuroinflammation, brain, brain cells

## **Chapter 2**

## Polyunsaturated Fatty Acid Metabolism in the Brain and Brain Cells

*Corinne Joffre*

## **Abstract**

Dietary polyunsaturated fatty acids (PUFAs) have gained more importance these last decades since they regulate the level of long-chain PUFAs (LC-PUFAs) in all cells and especially in brain cells. Because LC-PUFAs, especially those of the n-3 family, display both anti-inflammatory and pro-resolution properties, they play an essential role in neuroinflammation. Neuroinflammation is a hallmark of neurological disorders and requires to be tightly controlled or at least limited otherwise it can have functional consequences and negatively impact the quality of life and well-being of patients. LC-PUFAs exert these beneficial properties in part through the synthesis of specialized pro-resolving mediators (SPMs) that are involved in the resolution of inflammation and to the return of homeostasis. SPMs are promising relevant candidates to resolve brain inflammation and to contribute to neuroprotective functions and lead to novel therapeutics for brain inflammatory diseases. Here we present an overview of the origin and accumulation of PUFAs in the brain and brain cells and their conversion into SPMs that are involved in neuroinflammation and how nutrition induces variations in LC-PUFA and SPM levels in the brain and in brain cells.

**Keywords:** long-chain polyunsaturated fatty acids (LC-PUFAs), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), specialized pro-resolving mediators (SPMs), nutrition, neuroinflammation, brain, brain cells

## **1. Introduction**

Polyunsaturated fatty acids (PUFA) are essential fatty acids including precursors and long-chain PUFAs (LC-PUFAs). Precursors have to be provided by the diet because they cannot be produced by mammals [1]. They can be converted into LC-PUFAs. However, as the conversion rate is very low in human [2, 3], it is recommended to consume also LC-PUFAs that modulate LC-PUFA composition of brain and brain cells. Altered dietary intake and/or PUFA metabolism has been reported to be involved in a number of neurological disorders *via* sustained neuroinflammatory processes [4]. Indeed, LC-PUFAs are key regulators of inflammation [5]. LC-PUFAs can be metabolized into specific derivatives such as specialized proresolving mediators (SPMs) that have anti-inflammatory and pro-resolving properties [6–9], giving the LC-PUFAs and their biological derivatives a growing interest to treat inflammation and more specifically neuroinflammation. Hence, they may

represent a relevant alternative or complementary strategy to treat pathologies involving neuroinflammation. Here, we will review the literature on PUFAs and their bioactive lipid derivatives in the brain and brain cells. The book chapter will be divided in two main sections: in the first one, we will report data on the origin of PUFAs in the brain and on PUFA content in brain and brain cells and in the second one, we will review recent data on the bioactive lipid derivatives and their role in neuroinflammation. We will discuss how nutrition, an environmental factor to which individuals are exposed throughout their life, is a factor of variation of PUFA and their mediator contents in both sections. We will focus on total brain but also on brain cells since brain cells are differently affected by dietary supply.

## **2. PUFAs in the brain and brain cells**

## **2.1 Origin of PUFAs in the brain**

## *2.1.1 Metabolism of PUFAs*

PUFAs are fatty acids containing more than one double bond on their carbon chain. They are classified into two main series, the n-6 PUFAs and the n-3 PUFAs depending on the position of the first double bond from the methyl terminal end. N-6 PUFAs have the first double bond at the 6th carbon and n-3 PUFAs at the 3rd. Of these two series, linoleic acid (LA) and alpha-linolenic acid (ALA) are the precursors and are essential fatty acids because mammals cannot synthesize them. *In vivo*, these precursors can be elongated, desaturated and beta-oxidized into fatty acids with additional double bonds and carbon atoms leading to longchain PUFAs (LC-PUFAs, ≥20 carbon atoms) (**Figure 1**). This metabolic pathway requires specific Δ6 and Δ5 desaturases and elongases that are common to both n-6 and n-3 PUFAs, meaning that these pathways are in competition [10]. LC-PUFA

#### **Figure 1.**

*Synthesis pathways of n-6 and n-3 LC-PUFA and main dietary sources of PUFAs. LA: linoleic acid; LNA: linolenic acid; AA: arachidonic acid; EPA: eicosapentaenoic acid; DHA: docosahexaenoic acid.*

**15**

*Polyunsaturated Fatty Acid Metabolism in the Brain and Brain Cells*

triglycerides [29, 30]. More studies have to be performed.

The brain contains high levels of PUFAs (25–30%) that are mainly DHA (n-3 PUFA) (12–14% of total fatty acids) and AA (n-6 PUFA) (8–10% of total fatty acids) [12, 31–35]. Most LC-PUFAs accumulate during brain development, especially

**2.2 PUFA content in the brain**

biosynthesis takes place mainly in the liver, especially in both microsomes and peroxisomes [11]. However, the brain also possesses the enzymatic equipment and can synthesize LC-PUFAs. The main LC-PUFAs for the n-6 and n-3 series, due to their role as precursors of bioactive derivatives and due to their level in the brain, are arachidonic acid (AA, 20:4 n-6) and docosahexaenoic acid (DHA, 22:6 n-3) [12, 13]. Eicosapentaenoic acid (EPA, 20:5 n-3) is also an important n-3 LC-PUFA as it is also a precursor of bioactive derivatives despite its low level in the brain because of its rapid β-oxidation [14]. Docosapentaenoic acid (DPA, 22:5 n-6) for the n-6 family is also relevant because it replaces DHA in the membranes in case of dietary n-3 PUFA deficiency. LC-PUFAs are mainly esterified in phospholipids. They are also present as free LC-PUFA in very low amount: 1 nmole/g tissue *versus*

The precursors LA and ALA are found mainly in vegetables, oils, and seeds (60% of LA in sunflower oil and 10% of ALA in rapeseed oil, for example) (**Figure 1**) [16, 17]. Although human can synthesize LC-PUFAs from these precursors, the conversion efficiency is very low (<5%) even in healthy adults [2, 3]. Hence, the main part of LC-PUFAs comes from the diet. AA is found in meats (5–10%) and eggs (15%) [18, 19] and DHA and EPA are found in fatty fishes (18.7% EPA + DHA in salmon, 32.9% EPA + DHA in tuna, for example) (**Figure 1**) [20]. However, lean fishes (sole, codfish, etc.) contain also appreciable amounts of DHA and EPA. Therefore, LC-PUFAs dietary intakes are crucial to maintain adequate levels of LC-PUFAs in membranes. That is why there are dietary recommendations for PUFAs. Dietary intakes recommend ~500 mg/day in EPA and DHA (2 portions of fish/week) and a ratio LA/ALA close to 4–5 to meet all the needs of the body into DHA and to protect against cardiovascular disease risk [21, 22]. Preclinical and clinical studies indicate that increasing dietary ALA and reducing LA are beneficial in increasing n-3 LC-PUFA bioavailability [23, 24]. Despite these recommendations, dietary n-3 PUFA intake is insufficient, both for the precursor ALA and the LC-PUFAs DHA and EPA. Indeed, in the western diet, there is an imbalance between n-6 and n-3 PUFAs leading to an n-3 PUFA consumption 12–20 times lower than n-6 PUFA consumption [10, 25]. This is due to the increased industrialization in the developed nations accompanied by changes in dietary habits. It is particularly characterized by an increase in LA and AA together with a decrease in ALA and DHA. A high intake of LA associated with a low intake of ALA leads to the accumulation of n-6 PUFAs, including AA. In case of severe n-3 PUFA deficiency, the expression of desaturases and elongases are upregulated in the liver in order to compensate and provide DHA to the brain [26, 27]. In addition, under dietary n-3 PUFA deficiency, the half-life of brain DHA is increased by twofold as under balanced diet [28]. Dietary lipids, representing 35–40% of total energy intake, are essentially found (90–95%) in the form of triglycerides (a glycerol backbone with three fatty acids). They are also found in the form of phospholipids (in which the 3-position on the glycerol is replaced by a phosphorylated alcohol function). There is still a debate concerning the better form to enhance EPA/ DHA bioavailability, krill oil as a source of phospholipids or fish oil as a source of

*DOI: http://dx.doi.org/10.5772/intechopen.88232*

10 μmoles/g [15].

*2.1.2 Dietary origin*

#### *Polyunsaturated Fatty Acid Metabolism in the Brain and Brain Cells DOI: http://dx.doi.org/10.5772/intechopen.88232*

biosynthesis takes place mainly in the liver, especially in both microsomes and peroxisomes [11]. However, the brain also possesses the enzymatic equipment and can synthesize LC-PUFAs. The main LC-PUFAs for the n-6 and n-3 series, due to their role as precursors of bioactive derivatives and due to their level in the brain, are arachidonic acid (AA, 20:4 n-6) and docosahexaenoic acid (DHA, 22:6 n-3) [12, 13]. Eicosapentaenoic acid (EPA, 20:5 n-3) is also an important n-3 LC-PUFA as it is also a precursor of bioactive derivatives despite its low level in the brain because of its rapid β-oxidation [14]. Docosapentaenoic acid (DPA, 22:5 n-6) for the n-6 family is also relevant because it replaces DHA in the membranes in case of dietary n-3 PUFA deficiency. LC-PUFAs are mainly esterified in phospholipids. They are also present as free LC-PUFA in very low amount: 1 nmole/g tissue *versus* 10 μmoles/g [15].

## *2.1.2 Dietary origin*

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

on brain cells since brain cells are differently affected by dietary supply.

PUFAs are fatty acids containing more than one double bond on their carbon chain. They are classified into two main series, the n-6 PUFAs and the n-3 PUFAs depending on the position of the first double bond from the methyl terminal end. N-6 PUFAs have the first double bond at the 6th carbon and n-3 PUFAs at the 3rd. Of these two series, linoleic acid (LA) and alpha-linolenic acid (ALA) are the precursors and are essential fatty acids because mammals cannot synthesize them. *In vivo*, these precursors can be elongated, desaturated and beta-oxidized into fatty acids with additional double bonds and carbon atoms leading to longchain PUFAs (LC-PUFAs, ≥20 carbon atoms) (**Figure 1**). This metabolic pathway requires specific Δ6 and Δ5 desaturases and elongases that are common to both n-6 and n-3 PUFAs, meaning that these pathways are in competition [10]. LC-PUFA

*Synthesis pathways of n-6 and n-3 LC-PUFA and main dietary sources of PUFAs. LA: linoleic acid; LNA:* 

*linolenic acid; AA: arachidonic acid; EPA: eicosapentaenoic acid; DHA: docosahexaenoic acid.*

**2. PUFAs in the brain and brain cells**

**2.1 Origin of PUFAs in the brain**

*2.1.1 Metabolism of PUFAs*

represent a relevant alternative or complementary strategy to treat pathologies involving neuroinflammation. Here, we will review the literature on PUFAs and their bioactive lipid derivatives in the brain and brain cells. The book chapter will be divided in two main sections: in the first one, we will report data on the origin of PUFAs in the brain and on PUFA content in brain and brain cells and in the second one, we will review recent data on the bioactive lipid derivatives and their role in neuroinflammation. We will discuss how nutrition, an environmental factor to which individuals are exposed throughout their life, is a factor of variation of PUFA and their mediator contents in both sections. We will focus on total brain but also

**14**

**Figure 1.**

The precursors LA and ALA are found mainly in vegetables, oils, and seeds (60% of LA in sunflower oil and 10% of ALA in rapeseed oil, for example) (**Figure 1**) [16, 17]. Although human can synthesize LC-PUFAs from these precursors, the conversion efficiency is very low (<5%) even in healthy adults [2, 3]. Hence, the main part of LC-PUFAs comes from the diet. AA is found in meats (5–10%) and eggs (15%) [18, 19] and DHA and EPA are found in fatty fishes (18.7% EPA + DHA in salmon, 32.9% EPA + DHA in tuna, for example) (**Figure 1**) [20]. However, lean fishes (sole, codfish, etc.) contain also appreciable amounts of DHA and EPA. Therefore, LC-PUFAs dietary intakes are crucial to maintain adequate levels of LC-PUFAs in membranes. That is why there are dietary recommendations for PUFAs. Dietary intakes recommend ~500 mg/day in EPA and DHA (2 portions of fish/week) and a ratio LA/ALA close to 4–5 to meet all the needs of the body into DHA and to protect against cardiovascular disease risk [21, 22]. Preclinical and clinical studies indicate that increasing dietary ALA and reducing LA are beneficial in increasing n-3 LC-PUFA bioavailability [23, 24]. Despite these recommendations, dietary n-3 PUFA intake is insufficient, both for the precursor ALA and the LC-PUFAs DHA and EPA. Indeed, in the western diet, there is an imbalance between n-6 and n-3 PUFAs leading to an n-3 PUFA consumption 12–20 times lower than n-6 PUFA consumption [10, 25]. This is due to the increased industrialization in the developed nations accompanied by changes in dietary habits. It is particularly characterized by an increase in LA and AA together with a decrease in ALA and DHA. A high intake of LA associated with a low intake of ALA leads to the accumulation of n-6 PUFAs, including AA. In case of severe n-3 PUFA deficiency, the expression of desaturases and elongases are upregulated in the liver in order to compensate and provide DHA to the brain [26, 27]. In addition, under dietary n-3 PUFA deficiency, the half-life of brain DHA is increased by twofold as under balanced diet [28]. Dietary lipids, representing 35–40% of total energy intake, are essentially found (90–95%) in the form of triglycerides (a glycerol backbone with three fatty acids). They are also found in the form of phospholipids (in which the 3-position on the glycerol is replaced by a phosphorylated alcohol function). There is still a debate concerning the better form to enhance EPA/ DHA bioavailability, krill oil as a source of phospholipids or fish oil as a source of triglycerides [29, 30]. More studies have to be performed.

### **2.2 PUFA content in the brain**

The brain contains high levels of PUFAs (25–30%) that are mainly DHA (n-3 PUFA) (12–14% of total fatty acids) and AA (n-6 PUFA) (8–10% of total fatty acids) [12, 31–35]. Most LC-PUFAs accumulate during brain development, especially during the perinatal period: in humans between the beginning of the third trimester of gestation and 2 years and in rodents between the 7th and the 21st postnatal day [36–38]. These periods correspond to the rapid neuronal maturation, synaptogenesis, and gray matter expansion [39, 40]. The brain LC-PUFA content differs in brain structures [12, 31, 35, 41, 42], for example, in the adult C57Bl6/J mice, AA is higher in hippocampus (10.2%), followed by the prefrontal cortex (9.7%), the hypothalamus (8.5%), the cortex (7.7%), the cerebellum (6.5%), and the brain stem (5.5%) [12]. DHA is higher in the prefrontal cortex (14.3%) and in the hippocampus (13.7%), followed by cerebellum (12.2%) and cortex (11.9%), hypothalamus (10.1%), and brain stem (8.2%) [12]. Then the AA/DHA ratio varies from 0.75 to 0.85 in the hypothalamus and hippocampus to 0.54 in the cerebellum. These variations may be due to different LC-PUFA entry mechanisms into the brain or to different incorporation into membranes of cells composing the structure considered. These levels are comparable in human: prefrontal cortex contains between 12.3 and 15.9% of DHA in rats and mice and between 14.1 and 15.9% [12, 35, 43, 44].

## **2.3 PUFA content in brain cells**

Brain cells comprise neurons and glial cells: 70% astrocytes, 10–15% oligodendrocytes, and 10–15% microglial cells [45]. Very few studies reported the fatty acid composition of the individual cells. Bourre et al. determined the fatty acid composition in neurons, astrocytes, and oligodendrocytes in 15- or 60-days rats and confirmed previous results obtained in 1973 and 1981 [46–49]. We recently described the fatty acid composition of microglial cells in 21-days mice [46, 50].

Neurons cannot synthesize LC-PUFAs but can incorporate them in their membranes. They contain 8.2–8.3% DHA and 2.2–2.8% n-3 DPA (22:5 n-3) for n-3 LC-PUFAs, 10.3–15.1% AA, 2.2% n-6 DPA, and 1.0–2.1% adrenic acid (22: 4 n-6) for n-6 LC-PUFAs [46]. They contain 3.1–6.9% LA. Then the ratio n-3/n-6 is 0.46–0.50.

Astrocytes are supportive glial cells that play many roles including synaptic transmission and energy metabolite furniture to different neural elements. They respond to all forms of central nervous system (CNS) insults through a process referred to as reactive astrogliosis. Dysfunctions of astrocytes result in pathological changes in the CNS. Astrocytes contain 10.6–12.1% DHA and 0.7–1.3% of n-3 DPA for n-3 LC-PUFAs and 10.1–10.3% of AA, 2.5–2.7% of n-6 DPA and 2.4–2.7% adrenic acid (22:4 n-6) [46]. They contain few PUFA precursors: only 1.2–1.4% of LA and no ALA. The ratio n-3/n-6 is 0.72–0.76.

Oligodendrocytes provide a supporting role for neurons and are involved in the formation of myelin sheaths of nerve cell axons. They are highly dynamic and can respond to environmental influences and neuronal activity. They can also regenerate myelin spontaneously after CNS injury. Any disturbances in their functioning are associated with major diseases of the nervous system. They contain mainly 5.1% DHA for n-3 LC-PUFAs and 9.3% AA and 3.5% n-6 DPA for n-6 LC-PUFAs [46]. They contain not as much as LA: only 2.7%. The ratio n-3/n-6 is 0.33.

Microglial cells are the innate immune cells of the brain. They play a major role in synaptogenesis, synapse structure and function, and neuroinflammation. They perpetually scan and control their environment and once activated, they deliver pro-inflammatory and pro-regeneration responses. Their fatty acid composition differs from that of the other brain cells. In all these cells, DHA is the main fatty acid. Microglial cells are characterized by few DHA (<1%) and n-3 DPA (0.1%) but high content of EPA (3.7%) [50]. They contain few AA (1.6%). They contain PUFA precursors: 8.0% LA and 1.3% ALA. The ratio n-3/n-6 is 0.42. This microglial fatty acid composition also differs from the whole brain hippocampus that contains higher DHA than EPA [51]. Then, it seems that EPA metabolism is different in microglial cells than in other brain cells and the

**17**

*Polyunsaturated Fatty Acid Metabolism in the Brain and Brain Cells*

have to be performed to elucidate the role of EPA in microglial cells.

whole brain structure. It is not highly β-oxidized as in the whole brain [52]. More studies

**2.4 Nutrition as a major factor of variation of brain and brain cell PUFA content**

Nutrition is an environmental factor to which individuals are continuously exposed throughout life. And it is an environmental factor that changed a lot these last decades. Indeed, there was a dramatic reduction in the dietary supply of n-3 PUFAs in western societies associated with a drastic increase in the n-6 PUFAs, leading to an imbalanced n-6/n-3 PUFA ratio estimated at 12–20 in developed

This is particularly important considering that brain fatty acid composition varies with the fatty acids of the dietary supply [53]. Indeed, PUFA content is strongly impacted by the dietary PUFAs in all brain structures [12, 54]. A diet deficient in n-3 PUFA precursor during development and/or adulthood decreases brain DHA in all brain structures; the prefrontal cortex and the hippocampus that contain the highest DHA content are the most sensitive whereas the hypothalamus that contains the lowest DHA, is the least sensitive [12, 31, 55–58]. These differences may be attributed to the evolution of brain performance [59, 60]. In such case of n-3 PUFA deficiency, changes in metabolism occur: the half-life of DHA increases in the brain to reduce its loss [61] and the activity of DHA synthesis enzymes (Δ6 destaurase and elongase) is increased in the liver [26, 62, 63]. In contrast to the deficiency, the supplementation in n-3 LC-PUFAs increases brain DHA [64–67]. DHA supplementation is more efficient than ALA supplementation to increase brain DHA [68, 69]. A DHA supplementation is also efficient to reverse brain DHA decrease due to an n-3 PUFA deficiency or to aging [33, 70–72]. Also, genetic models of n-3 PUFA enrichment such as Fat-1 mice possess higher brain DHA content [12, 73–77].

Brain cells are also impacted by dietary PUFA supply. An n-3 PUFA precursor-

All these results suggest that brain DHA levels are highly variables, depending on the brain structures or brain cells considered and on the dietary fatty acid intake. This may have consequences on inflammatory processes since n-3 LC-PUFAs have

Some of the immunomodulatory properties of LC-PUFAs are attributed to the synthesis of bioactive lipid mediators. Different lipid mediators are synthesized: those

deficient diet decreases DHA in neurons (4.6% *versus* 8.2% in 15-day old animals and 2.4 *versus* 8.3% in 60-day old animals), astrocytes (3.1 *versus* 10.6% in 15-day old animals and 5.7 *versus* 12.1% in 60-day old animals), and oligodendrocytes (0.1% *versus* 5.1% in 60-day old animals) [46]. These changes decrease the n-3/n-6 ratio (0.24 *versus* 0.46–0.50 in neurons, 0.12–0.25 *versus* 0.72–0.76 in astrocytes and 0.02 *versus* 0.33 in oligodendrocytes). Interestingly, we recently find that a maternal n-3 PUFA precursor deficiency increases n-6 DPA but does not affect DHA level in microglial cells in 21-day-old animals, suggesting that these cells are protected from n-3 PUFA deficiency [50]. However, we also report that a maternal n-3 LC-PUFA supplementation increases DHA levels and decreases n-6 DPA levels in these animals, confirming results previously obtained in glial cells [78, 79].

*DOI: http://dx.doi.org/10.5772/intechopen.88232*

countries instead of five recommended [10].

immunomodulatory properties [80].

**3. Bioactive PUFA derivatives**

**3.1 Bioactive PUFA derivative metabolism**

*3.1.1 PUFA derivative synthesis pathways*

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

during the perinatal period: in humans between the beginning of the third trimester of gestation and 2 years and in rodents between the 7th and the 21st postnatal day [36–38]. These periods correspond to the rapid neuronal maturation, synaptogenesis, and gray matter expansion [39, 40]. The brain LC-PUFA content differs in brain structures [12, 31, 35, 41, 42], for example, in the adult C57Bl6/J mice, AA is higher in hippocampus (10.2%), followed by the prefrontal cortex (9.7%), the hypothalamus (8.5%), the cortex (7.7%), the cerebellum (6.5%), and the brain stem (5.5%) [12]. DHA is higher in the prefrontal cortex (14.3%) and in the hippocampus (13.7%), followed by cerebellum (12.2%) and cortex (11.9%), hypothalamus (10.1%), and brain stem (8.2%) [12]. Then the AA/DHA ratio varies from 0.75 to 0.85 in the hypothalamus and hippocampus to 0.54 in the cerebellum. These variations may be due to different LC-PUFA entry mechanisms into the brain or to different incorporation into membranes of cells composing the structure considered. These levels are comparable in human: prefrontal cortex contains between 12.3 and

15.9% of DHA in rats and mice and between 14.1 and 15.9% [12, 35, 43, 44].

the fatty acid composition of microglial cells in 21-days mice [46, 50].

They contain not as much as LA: only 2.7%. The ratio n-3/n-6 is 0.33.

LA and no ALA. The ratio n-3/n-6 is 0.72–0.76.

Brain cells comprise neurons and glial cells: 70% astrocytes, 10–15% oligodendrocytes, and 10–15% microglial cells [45]. Very few studies reported the fatty acid composition of the individual cells. Bourre et al. determined the fatty acid composition in neurons, astrocytes, and oligodendrocytes in 15- or 60-days rats and confirmed previous results obtained in 1973 and 1981 [46–49]. We recently described

Neurons cannot synthesize LC-PUFAs but can incorporate them in their membranes. They contain 8.2–8.3% DHA and 2.2–2.8% n-3 DPA (22:5 n-3) for n-3 LC-PUFAs, 10.3–15.1% AA, 2.2% n-6 DPA, and 1.0–2.1% adrenic acid (22: 4 n-6) for n-6 LC-PUFAs [46]. They contain 3.1–6.9% LA. Then the ratio n-3/n-6 is 0.46–0.50. Astrocytes are supportive glial cells that play many roles including synaptic transmission and energy metabolite furniture to different neural elements. They respond to all forms of central nervous system (CNS) insults through a process referred to as reactive astrogliosis. Dysfunctions of astrocytes result in pathological changes in the CNS. Astrocytes contain 10.6–12.1% DHA and 0.7–1.3% of n-3 DPA for n-3 LC-PUFAs and 10.1–10.3% of AA, 2.5–2.7% of n-6 DPA and 2.4–2.7% adrenic acid (22:4 n-6) [46]. They contain few PUFA precursors: only 1.2–1.4% of

Oligodendrocytes provide a supporting role for neurons and are involved in the formation of myelin sheaths of nerve cell axons. They are highly dynamic and can respond to environmental influences and neuronal activity. They can also regenerate myelin spontaneously after CNS injury. Any disturbances in their functioning are associated with major diseases of the nervous system. They contain mainly 5.1% DHA for n-3 LC-PUFAs and 9.3% AA and 3.5% n-6 DPA for n-6 LC-PUFAs [46].

Microglial cells are the innate immune cells of the brain. They play a major role in synaptogenesis, synapse structure and function, and neuroinflammation. They perpetually scan and control their environment and once activated, they deliver pro-inflammatory and pro-regeneration responses. Their fatty acid composition differs from that of the other brain cells. In all these cells, DHA is the main fatty acid. Microglial cells are characterized by few DHA (<1%) and n-3 DPA (0.1%) but high content of EPA (3.7%) [50]. They contain few AA (1.6%). They contain PUFA precursors: 8.0% LA and 1.3% ALA. The ratio n-3/n-6 is 0.42. This microglial fatty acid composition also differs from the whole brain hippocampus that contains higher DHA than EPA [51]. Then, it seems that EPA metabolism is different in microglial cells than in other brain cells and the

**2.3 PUFA content in brain cells**

**16**

whole brain structure. It is not highly β-oxidized as in the whole brain [52]. More studies have to be performed to elucidate the role of EPA in microglial cells.

### **2.4 Nutrition as a major factor of variation of brain and brain cell PUFA content**

Nutrition is an environmental factor to which individuals are continuously exposed throughout life. And it is an environmental factor that changed a lot these last decades. Indeed, there was a dramatic reduction in the dietary supply of n-3 PUFAs in western societies associated with a drastic increase in the n-6 PUFAs, leading to an imbalanced n-6/n-3 PUFA ratio estimated at 12–20 in developed countries instead of five recommended [10].

This is particularly important considering that brain fatty acid composition varies with the fatty acids of the dietary supply [53]. Indeed, PUFA content is strongly impacted by the dietary PUFAs in all brain structures [12, 54]. A diet deficient in n-3 PUFA precursor during development and/or adulthood decreases brain DHA in all brain structures; the prefrontal cortex and the hippocampus that contain the highest DHA content are the most sensitive whereas the hypothalamus that contains the lowest DHA, is the least sensitive [12, 31, 55–58]. These differences may be attributed to the evolution of brain performance [59, 60]. In such case of n-3 PUFA deficiency, changes in metabolism occur: the half-life of DHA increases in the brain to reduce its loss [61] and the activity of DHA synthesis enzymes (Δ6 destaurase and elongase) is increased in the liver [26, 62, 63]. In contrast to the deficiency, the supplementation in n-3 LC-PUFAs increases brain DHA [64–67]. DHA supplementation is more efficient than ALA supplementation to increase brain DHA [68, 69]. A DHA supplementation is also efficient to reverse brain DHA decrease due to an n-3 PUFA deficiency or to aging [33, 70–72]. Also, genetic models of n-3 PUFA enrichment such as Fat-1 mice possess higher brain DHA content [12, 73–77].

Brain cells are also impacted by dietary PUFA supply. An n-3 PUFA precursordeficient diet decreases DHA in neurons (4.6% *versus* 8.2% in 15-day old animals and 2.4 *versus* 8.3% in 60-day old animals), astrocytes (3.1 *versus* 10.6% in 15-day old animals and 5.7 *versus* 12.1% in 60-day old animals), and oligodendrocytes (0.1% *versus* 5.1% in 60-day old animals) [46]. These changes decrease the n-3/n-6 ratio (0.24 *versus* 0.46–0.50 in neurons, 0.12–0.25 *versus* 0.72–0.76 in astrocytes and 0.02 *versus* 0.33 in oligodendrocytes). Interestingly, we recently find that a maternal n-3 PUFA precursor deficiency increases n-6 DPA but does not affect DHA level in microglial cells in 21-day-old animals, suggesting that these cells are protected from n-3 PUFA deficiency [50]. However, we also report that a maternal n-3 LC-PUFA supplementation increases DHA levels and decreases n-6 DPA levels in these animals, confirming results previously obtained in glial cells [78, 79].

All these results suggest that brain DHA levels are highly variables, depending on the brain structures or brain cells considered and on the dietary fatty acid intake. This may have consequences on inflammatory processes since n-3 LC-PUFAs have immunomodulatory properties [80].

#### **3. Bioactive PUFA derivatives**

#### **3.1 Bioactive PUFA derivative metabolism**

#### *3.1.1 PUFA derivative synthesis pathways*

Some of the immunomodulatory properties of LC-PUFAs are attributed to the synthesis of bioactive lipid mediators. Different lipid mediators are synthesized: those involved in the regulation of inflammation such as the eicosanoids (prostaglandins, leukotrienes, and thromboxanes) and those implicated in the resolution of inflammation called specialized pro-resolving mediators (SPMs, resolvins, protectins, and maresins) (**Figure 2**). Among the eicosanoids, those synthesized from n-3 PUFAs are less potent inflammatory than those synthesized from n-6 PUFAs [81] highlighting the interest to increase n-3 PUFA and decrease n-6 PUFA contents in the membranes. Then, when co-present, EPA-derived eicosanoids antagonize those synthesized from AA. The main EPA-derived mediators include 3-series prostaglandin (PG), 5-series leukotriene (LT), and 3-series thromboxane (TX), reported to be nonactive (**Figure 2**). DHA is also converted into 3-series PG (**Figure 2**). In addition, eicosanoids synthesized from AA and EPA act in competition as they share the same G-protein-coupled receptors. Moreover, EPA is a competitive inhibitor to AA. Indeed, it reduces the production of AA by inhibiting the activity of Δ5 desaturase converting dihomo-gamma-linolenic acid (dGLA) into AA [81]. EPA also reduces *in vitro* the production of AA-derived eicosanoids by inhibiting the activity of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) generating the eicosanoids [82–84]. Eicosanoids are synthesized first in the time course of the inflammatory response. Then, there is a switch in the bioactive lipid mediator class: SPMs derived from n-3 LC-PUFAs are synthesized to induce the resolution of inflammation and a return to homeostasis (**Figure 3**). DHA is the precursor of D-series resolvins, neuroprotectin D1 (NPD1), and Maresin 1–2 (Mar1–2) and EPA is the precursor of E-series resolvins, all these derivatives underlying most of the beneficial effects attributed to their precursors [1, 85–87]. These derivatives have both anti-inflammatory and pro-resolution properties without immune suppression [6, 8, 88, 89]. SPMs actively orchestrate and finely tune the inflammatory response. They decrease pro-inflammatory cytokines and increase anti-inflammatory cytokines and accelerate the phagocytosis of cellular debris and dead cells without immune suppression. They are synthesized *via* COX-2, LOX, and cytochrome P450 monooxygenases (CYP450) once they have been released from membrane phospholipids by phospholipase A2 in response to stimulation. These

#### **Figure 2.**

*Main bioactive lipid mediators synthesized from n-3 PUFAs. DHA: docosahexaenoic acid; EPA: eicosapentaenoic acid; LNA: linolenic acid; LT: leukotriene; NPD1: neuroprotection D1; PG: prostaglandin; SPMs: specialized pro-resolving mediators; Tx: thromboxane.*

**19**

*Polyunsaturated Fatty Acid Metabolism in the Brain and Brain Cells*

enzymes are expressed in the brain [90–92]. In response to lipopolysaccharide (LPS) that induces inflammation, COX-2 is rapidly expressed in the hippocampus [69, 93] and inhibition of COX-2 delays resolution of acute inflammation [94]. 15-LOX and 5-LOX are the most abundant LOX in the brain [90]. 15-LOX has a dual role since it is involved in neurodegeneration and neurotoxicity due to the increased stress it generates [95–97] and is also involved in neuroprotection [98]. 15-LOX deletion or inhibition decreases SPM production in the brain and cognitive alterations [90]. CYP450 generates n-6 derived epoxides that are anti-inflammatory [99–102]. These enzymes are also expressed in microglia, astrocytes, oligodendrocytes, and neurons [103–106].

DHA is converted into monohydroxy DHA (17-HDHA) by acetylated COX-2, CYP450, and 15-LOX [107, 108] and then into RvD1 by 5-LOX [109, 110]. RvD1 and its precursors have mostly been described at the periphery but have also been detected in the brain. RvD1 was measured in mouse brain following cerebral ischemia. Its level is increased following a DHA intravenous injection [111] and modulated during inflammation: it decreases at the beginning and then increases during the resolution phase [112]. RvD1 acts through the regulation of micro-RNAs (miRNAs) that modulate the expression of target genes such as inflammatory genes [113–117]. DHA can also be converted into di-hydroxy-DHA termed protectin D1 (PD1) or neuroprotectin D1 (NPD1) when produced in the CNS by 5- and 15-LOX [118–121]. NPD1 was measured in hippocampus. Its level greatly is increased following brain ischemia or acute central LPS injection [70, 122] and decreased in the hippocampus of Alzheimer's disease patients [123]. NPD1 acts through NFkB and then decreases pro-inflammatory gene expression [122, 124, 125]. At last, DHA can also be converted into 14-HDHA and then in Mar1–2 by 12/15-LOX [107, 108, 126]. Mar1 and its precursor 14-HDHA have recently been identified in the hippocampus of mice [70]. Its level is decreased in post-mortem Alzheimer's disease patients contributing to the progression of this pathology [127]. Mar1 promotes the resolution of inflammation, reducing pro-inflammatory cytokines, silencing pro-inflammatory signaling cascades, and enhancing M2 repair macrophage phenotype after cerebral ischemia or spinal cord injury

EPA is converted into resolvins E1, E2, and E3 by acetylated COX-2 or CYP450 *via* 18R-HEPE by 5- or 15-LOX [107, 131, 132]. RvE1 and its precursor have been detected in hippocampus [70, 133, 134]. RvE1 inhibits NFκB signaling pathway and then decreases LPS-induced proinflammatory cytokines (TNF-α, IL-6, and IL-1β)

SPMs act through specific receptors, some but not all of them have recently been identified. RvD1 acts through lipoxin A4 receptor/formyl peptide receptor 2 (ALX/ Fpr2) in rodents and G protein coupling receptor 32 (GPR32) in human [109] at picomolar range but induces biological effects at nanomolar range [110, 135]. RvE1 directly binds to its receptor G protein coupling receptor ChemR23 or chemokine like receptor 1 (CMKLR1) [131]. It is also a partial agonist of a leukotriene B4 receptor (BLT1) [136]. In the CNS, ALX/Fpr2 has been identified in the brainstem, spinal cord, hypothalamus, cortex, hippocampus, cerebellum, and striatum [137] and ChemR23 in the prefrontal cortex, hippocampus, and brainstem [138]. At the cellular levels, these two receptors have been detected in microglial cells [117, 139],

*DOI: http://dx.doi.org/10.5772/intechopen.88232*

*3.1.2 Bioactive lipid mediators*

[128–130] (**Figure 3**).

*3.1.3 SPM receptors*

gene expression in microglial cells [117].

neurons [137, 140] and astrocytes [96, 113] (**Figure 3**).

#### *Polyunsaturated Fatty Acid Metabolism in the Brain and Brain Cells DOI: http://dx.doi.org/10.5772/intechopen.88232*

enzymes are expressed in the brain [90–92]. In response to lipopolysaccharide (LPS) that induces inflammation, COX-2 is rapidly expressed in the hippocampus [69, 93] and inhibition of COX-2 delays resolution of acute inflammation [94]. 15-LOX and 5-LOX are the most abundant LOX in the brain [90]. 15-LOX has a dual role since it is involved in neurodegeneration and neurotoxicity due to the increased stress it generates [95–97] and is also involved in neuroprotection [98]. 15-LOX deletion or inhibition decreases SPM production in the brain and cognitive alterations [90]. CYP450 generates n-6 derived epoxides that are anti-inflammatory [99–102]. These enzymes are also expressed in microglia, astrocytes, oligodendrocytes, and neurons [103–106].

## *3.1.2 Bioactive lipid mediators*

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

*Main bioactive lipid mediators synthesized from n-3 PUFAs. DHA: docosahexaenoic acid; EPA:* 

*SPMs: specialized pro-resolving mediators; Tx: thromboxane.*

*eicosapentaenoic acid; LNA: linolenic acid; LT: leukotriene; NPD1: neuroprotection D1; PG: prostaglandin;* 

involved in the regulation of inflammation such as the eicosanoids (prostaglandins, leukotrienes, and thromboxanes) and those implicated in the resolution of inflammation called specialized pro-resolving mediators (SPMs, resolvins, protectins, and maresins) (**Figure 2**). Among the eicosanoids, those synthesized from n-3 PUFAs are less potent inflammatory than those synthesized from n-6 PUFAs [81] highlighting the interest to increase n-3 PUFA and decrease n-6 PUFA contents in the membranes. Then, when co-present, EPA-derived eicosanoids antagonize those synthesized from AA. The main EPA-derived mediators include 3-series prostaglandin (PG), 5-series leukotriene (LT), and 3-series thromboxane (TX), reported to be nonactive (**Figure 2**). DHA is also converted into 3-series PG (**Figure 2**). In addition, eicosanoids synthesized from AA and EPA act in competition as they share the same G-protein-coupled receptors. Moreover, EPA is a competitive inhibitor to AA. Indeed, it reduces the production of AA by inhibiting the activity of Δ5 desaturase converting dihomo-gamma-linolenic acid (dGLA) into AA [81]. EPA also reduces *in vitro* the production of AA-derived eicosanoids by inhibiting the activity of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) generating the eicosanoids [82–84]. Eicosanoids are synthesized first in the time course of the inflammatory response. Then, there is a switch in the bioactive lipid mediator class: SPMs derived from n-3 LC-PUFAs are synthesized to induce the resolution of inflammation and a return to homeostasis (**Figure 3**). DHA is the precursor of D-series resolvins, neuroprotectin D1 (NPD1), and Maresin 1–2 (Mar1–2) and EPA is the precursor of E-series resolvins, all these derivatives underlying most of the beneficial effects attributed to their precursors [1, 85–87]. These derivatives have both anti-inflammatory and pro-resolution properties without immune suppression [6, 8, 88, 89]. SPMs actively orchestrate and finely tune the inflammatory response. They decrease pro-inflammatory cytokines and increase anti-inflammatory cytokines and accelerate the phagocytosis of cellular debris and dead cells without immune suppression. They are synthesized *via* COX-2, LOX, and cytochrome P450 monooxygenases (CYP450) once they have been released from membrane phospholipids by phospholipase A2 in response to stimulation. These

**18**

**Figure 2.**

DHA is converted into monohydroxy DHA (17-HDHA) by acetylated COX-2, CYP450, and 15-LOX [107, 108] and then into RvD1 by 5-LOX [109, 110]. RvD1 and its precursors have mostly been described at the periphery but have also been detected in the brain. RvD1 was measured in mouse brain following cerebral ischemia. Its level is increased following a DHA intravenous injection [111] and modulated during inflammation: it decreases at the beginning and then increases during the resolution phase [112]. RvD1 acts through the regulation of micro-RNAs (miRNAs) that modulate the expression of target genes such as inflammatory genes [113–117]. DHA can also be converted into di-hydroxy-DHA termed protectin D1 (PD1) or neuroprotectin D1 (NPD1) when produced in the CNS by 5- and 15-LOX [118–121]. NPD1 was measured in hippocampus. Its level greatly is increased following brain ischemia or acute central LPS injection [70, 122] and decreased in the hippocampus of Alzheimer's disease patients [123]. NPD1 acts through NFkB and then decreases pro-inflammatory gene expression [122, 124, 125]. At last, DHA can also be converted into 14-HDHA and then in Mar1–2 by 12/15-LOX [107, 108, 126]. Mar1 and its precursor 14-HDHA have recently been identified in the hippocampus of mice [70]. Its level is decreased in post-mortem Alzheimer's disease patients contributing to the progression of this pathology [127]. Mar1 promotes the resolution of inflammation, reducing pro-inflammatory cytokines, silencing pro-inflammatory signaling cascades, and enhancing M2 repair macrophage phenotype after cerebral ischemia or spinal cord injury [128–130] (**Figure 3**).

EPA is converted into resolvins E1, E2, and E3 by acetylated COX-2 or CYP450 *via* 18R-HEPE by 5- or 15-LOX [107, 131, 132]. RvE1 and its precursor have been detected in hippocampus [70, 133, 134]. RvE1 inhibits NFκB signaling pathway and then decreases LPS-induced proinflammatory cytokines (TNF-α, IL-6, and IL-1β) gene expression in microglial cells [117].

### *3.1.3 SPM receptors*

SPMs act through specific receptors, some but not all of them have recently been identified. RvD1 acts through lipoxin A4 receptor/formyl peptide receptor 2 (ALX/ Fpr2) in rodents and G protein coupling receptor 32 (GPR32) in human [109] at picomolar range but induces biological effects at nanomolar range [110, 135]. RvE1 directly binds to its receptor G protein coupling receptor ChemR23 or chemokine like receptor 1 (CMKLR1) [131]. It is also a partial agonist of a leukotriene B4 receptor (BLT1) [136]. In the CNS, ALX/Fpr2 has been identified in the brainstem, spinal cord, hypothalamus, cortex, hippocampus, cerebellum, and striatum [137] and ChemR23 in the prefrontal cortex, hippocampus, and brainstem [138]. At the cellular levels, these two receptors have been detected in microglial cells [117, 139], neurons [137, 140] and astrocytes [96, 113] (**Figure 3**).

**Figure 3.**

*Specialized pro-resolving mediator (SPM) synthesis. 14-HDHA: 14-hydroxy-docosahexaenoic acid; 17-HDHA: 17-hydroxy-docosahexaenoic acid; 18-HEPE: 18-hydroxy-eicosapentaenoic acid; ALX/Fpr2: N-formyl peptide receptor 2; BLT1: leukotriene B4 receptor; COX-2: cyclooxygenases; DHA: docosahexaenoic acid; EPA: eicosapentaenoic acid; GPR32/37: G protein-coupled receptor 32/37; LC-PUFAs: long chain polyunsaturated fatty acids; LOX: lipoxygenases.*

Other receptors have not been identified yet (Mar1 receptor) [127] or identified only at the periphery in macrophages but not in microglia (NPD1 receptor) [141].

In the next sections, we will focus on the role of these SPMs to better understand the beneficial effects of the n-3 PUFAs.

#### **3.2 Role of bioactive lipid derivatives in neuroinflammation**

SPMs have multiple biological roles, focusing to the return to homeostasis. In human serum, DHA- and EPA-derivatives represent 30.7 and 25.9% of the identified SPMs, respectively [142, 143]. The most SPMs studied are RvD1 and RvE1 because they have powerful anti-inflammatory and pro-resolution properties. We will then detail the biological roles for these two bioactive mediators.

#### *3.2.1 Biological role of RvD1 and RvE1 in humans*

The effect of RvD1 was mainly studied in patients suffering from Alzheimer's disease. Interestingly, RvD1 levels in cerebrospinal fluid are positively correlated with the enhancement of cognitive functions of patients with dementia [96]. Moreover, it was suggested *in vitro* in macrophages isolated from Alzheimer's patients that RvD1 may be involved in Aβ phagocytosis [144, 145]. Then the decrease in RvD1 levels in Alzheimer's patient brain could contribute to the disease development. To our knowledge, the effect of RvE1 in humans was shown at the periphery (on patients undergoing hepatobiliary resection, pulmonary

**21**

*Polyunsaturated Fatty Acid Metabolism in the Brain and Brain Cells*

on patients suffering from neurodegenerative diseases.

*3.2.2 Biological roles of RvD1 and RvE1 in rodents*

inflammation, and bone disease periodontitis) [146–148] but not at the brain level

RvD1 and RvE1 are active in reducing the pro-inflammatory status in the CNS. Indeed, the precursors of RvD1, 17R-HDHA, and 17S-HDHA decrease the production of pro-inflammatory cytokines TNF-α in the spinal cord and IL-1β and TNF-α in the hippocampus [70, 149]. Moreover, RvD1 is able to induce the polarization of macrophages and microglia toward an M2 phagocytic phenotype [150–152]. In addition, RvD1 reduces neuroinflammation *via* miRNA in a model of remote damage [113]. RvE1 also modulates inflammation by reducing the proinflammatory cytokines IL-1β and IL-6 in the prefrontal cortex and decreases the measures of Aβ pathology in a murine model of Alzheimer's disease [153]. Furthermore, RvE1 treatment decreases brain microglial activation following traumatic brain injury or peripheral brain injury, decreasing the proportion of activated microglia at the

RvD1 is also involved in the prevention of cognitive deficits. In a systemic inflammation model, cognitive decline is prevented by an intraperitoneal (ip) injection of the precursor of RvD1, 17R-HDHA, and is associated with the restoration of transmission and synaptic plasticity and to the prevention of astrogliosis [154, 156]. Moreover, in a model of traumatic brain injury, cognitive deficits are also prevented by an ip chronic administration of 17R-HDHA [154]. Of note, Fat-1 mice that have more brain n-3 LC-PUFAs have higher hippocampus RvD1 that is associated with less cognitive deficits, a better neuronal survival, a decrease in astrocyte and microglial activation and a reduction in pro-inflammatory status following brain ischemia [77, 157]. Inversely, an inhibition of 15-LOX associated with a decrease in

RvD1 induces alterations in synaptic plasticity and working memory [90].

*3.2.3 Biological roles of RvD1 and RvE1 in in vitro brain cell models*

Additionally, RvD and E are also associated with the prevention of depressivelike behaviors [158]. An intracerebroventricular (icv) injection of RvD1, D2, E1, E2, or E3 significantly decreases LPS-induced depressive-like behaviors [159–161]. Moreover, an intrathecal injection of 17R-HDHA prevents the occurrence of

depressive-like behaviors and is associated with the decrease of pain perception and a restoration of dopamine and glutamate levels in the brain [149, 162]. RvD1 and D2 have also positive effects in chronic mild stress-induced depression and in post-

The effects of RvD1 were tested on different brain cells. In microglial cells, RvD1 potentiates the activation of the anti-inflammatory M2 phenotype of microglia, enhancing the effect of the anti-inflammatory cytokine IL-4, Arg1, and Ym1 expression and decreasing CD11b expression [152, 155, 165]. Moreover, we showed that RvD1 decreases LPS-induced proinflammatory cytokine (TNFα, IL-6 and IL-1β) gene expression in microglial BV2 cells *via* the modulation of miRNAs [117]. RvD2 inhibits LPS-induced activation of toll-like receptor 4 (TLR4, the receptor of LPS) and its downstream signaling pathway NFκB [166]. RvE1 plays also a direct role in microglial cells by inhibiting microglial activation and pro-inflammatory cytokine release [117, 155]. These results suggest the proresolution activity of RvD1 and RvE1 in microglia. In astrocytes, RvD1 decreases TNF-α release induced by LPS injection [149]. In neurons from spinal nods, RvD1

*DOI: http://dx.doi.org/10.5772/intechopen.88232*

expense of ramified microglia [154, 155].

myocardial infarct depression [163, 164].

increases neurite outgrowth [167].

inflammation, and bone disease periodontitis) [146–148] but not at the brain level on patients suffering from neurodegenerative diseases.

## *3.2.2 Biological roles of RvD1 and RvE1 in rodents*

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

Other receptors have not been identified yet (Mar1 receptor) [127] or identified only at the periphery in macrophages but not in microglia (NPD1 receptor) [141]. In the next sections, we will focus on the role of these SPMs to better understand

*Specialized pro-resolving mediator (SPM) synthesis. 14-HDHA: 14-hydroxy-docosahexaenoic acid; 17-HDHA: 17-hydroxy-docosahexaenoic acid; 18-HEPE: 18-hydroxy-eicosapentaenoic acid; ALX/Fpr2: N-formyl peptide receptor 2; BLT1: leukotriene B4 receptor; COX-2: cyclooxygenases; DHA: docosahexaenoic acid; EPA: eicosapentaenoic acid; GPR32/37: G protein-coupled receptor 32/37; LC-PUFAs: long chain polyunsaturated* 

SPMs have multiple biological roles, focusing to the return to homeostasis. In human serum, DHA- and EPA-derivatives represent 30.7 and 25.9% of the identified SPMs, respectively [142, 143]. The most SPMs studied are RvD1 and RvE1 because they have powerful anti-inflammatory and pro-resolution properties. We

The effect of RvD1 was mainly studied in patients suffering from Alzheimer's disease. Interestingly, RvD1 levels in cerebrospinal fluid are positively correlated with the enhancement of cognitive functions of patients with dementia [96]. Moreover, it was suggested *in vitro* in macrophages isolated from Alzheimer's patients that RvD1 may be involved in Aβ phagocytosis [144, 145]. Then the decrease in RvD1 levels in Alzheimer's patient brain could contribute to the disease development. To our knowledge, the effect of RvE1 in humans was shown at the periphery (on patients undergoing hepatobiliary resection, pulmonary

the beneficial effects of the n-3 PUFAs.

*3.2.1 Biological role of RvD1 and RvE1 in humans*

**3.2 Role of bioactive lipid derivatives in neuroinflammation**

will then detail the biological roles for these two bioactive mediators.

**20**

**Figure 3.**

*fatty acids; LOX: lipoxygenases.*

RvD1 and RvE1 are active in reducing the pro-inflammatory status in the CNS. Indeed, the precursors of RvD1, 17R-HDHA, and 17S-HDHA decrease the production of pro-inflammatory cytokines TNF-α in the spinal cord and IL-1β and TNF-α in the hippocampus [70, 149]. Moreover, RvD1 is able to induce the polarization of macrophages and microglia toward an M2 phagocytic phenotype [150–152]. In addition, RvD1 reduces neuroinflammation *via* miRNA in a model of remote damage [113]. RvE1 also modulates inflammation by reducing the proinflammatory cytokines IL-1β and IL-6 in the prefrontal cortex and decreases the measures of Aβ pathology in a murine model of Alzheimer's disease [153]. Furthermore, RvE1 treatment decreases brain microglial activation following traumatic brain injury or peripheral brain injury, decreasing the proportion of activated microglia at the expense of ramified microglia [154, 155].

RvD1 is also involved in the prevention of cognitive deficits. In a systemic inflammation model, cognitive decline is prevented by an intraperitoneal (ip) injection of the precursor of RvD1, 17R-HDHA, and is associated with the restoration of transmission and synaptic plasticity and to the prevention of astrogliosis [154, 156]. Moreover, in a model of traumatic brain injury, cognitive deficits are also prevented by an ip chronic administration of 17R-HDHA [154]. Of note, Fat-1 mice that have more brain n-3 LC-PUFAs have higher hippocampus RvD1 that is associated with less cognitive deficits, a better neuronal survival, a decrease in astrocyte and microglial activation and a reduction in pro-inflammatory status following brain ischemia [77, 157]. Inversely, an inhibition of 15-LOX associated with a decrease in RvD1 induces alterations in synaptic plasticity and working memory [90].

Additionally, RvD and E are also associated with the prevention of depressivelike behaviors [158]. An intracerebroventricular (icv) injection of RvD1, D2, E1, E2, or E3 significantly decreases LPS-induced depressive-like behaviors [159–161]. Moreover, an intrathecal injection of 17R-HDHA prevents the occurrence of depressive-like behaviors and is associated with the decrease of pain perception and a restoration of dopamine and glutamate levels in the brain [149, 162]. RvD1 and D2 have also positive effects in chronic mild stress-induced depression and in postmyocardial infarct depression [163, 164].

### *3.2.3 Biological roles of RvD1 and RvE1 in in vitro brain cell models*

The effects of RvD1 were tested on different brain cells. In microglial cells, RvD1 potentiates the activation of the anti-inflammatory M2 phenotype of microglia, enhancing the effect of the anti-inflammatory cytokine IL-4, Arg1, and Ym1 expression and decreasing CD11b expression [152, 155, 165]. Moreover, we showed that RvD1 decreases LPS-induced proinflammatory cytokine (TNFα, IL-6 and IL-1β) gene expression in microglial BV2 cells *via* the modulation of miRNAs [117]. RvD2 inhibits LPS-induced activation of toll-like receptor 4 (TLR4, the receptor of LPS) and its downstream signaling pathway NFκB [166]. RvE1 plays also a direct role in microglial cells by inhibiting microglial activation and pro-inflammatory cytokine release [117, 155]. These results suggest the proresolution activity of RvD1 and RvE1 in microglia. In astrocytes, RvD1 decreases TNF-α release induced by LPS injection [149]. In neurons from spinal nods, RvD1 increases neurite outgrowth [167].

All these studies point out the central role of n-3 LC-PUFA and their bioactive mediators in the regulation of inflammation in the brain, especially through their effect on microglia.

#### **3.3 Nutrition as a factor of variation of SPM levels**

The level of these lipid derivatives is modulated by the diet. Indeed, we recently show that a dietary n-3 LC-PUFA supplementation induces an n-3 LC-PUFA enrichment in the hippocampus associated with an increase in n-3 PUFA-derived SPMs and a decrease in n-6 PUFA-derived SPMs [69]. Our results confirm previous ones reporting that oral administration of EPA and DHA results in the generation of EPA-and DHA-derived mediators in the cortex of aged rats [168] and in the downregulation of the production of n-6 PUFA-derived mediators [169, 170]. The cellular origin of these bioactive lipid derivatives is still unknown. As described in the paragraph above, we know that dietary PUFA supplementation affects PUFA composition in brain cells that potentially could impact brain cell PUFA lipid derivatives. In response to LPS, n-3 LC-PUFA-supplemented mice display an anti-inflammatory SPM profile whereas n-3 LC-PUFA-deficient mice exhibit a pro-inflammatory SPM profile [69]. These results corroborate previous ones *in vivo* [171–176] and *in vitro* in macrophages [177, 178] and microglia [179–181].

The level of SPMs is also dependent on the regulation of their biosynthesis enzymes. 15-LOX mRNA expression increases in n-3 LC-PUFA supplemented group and decreases in n-3 LC-PUFA deficient diet [27, 69, 182]. 15-LOX has beneficial properties such as neuroprotective properties *via* PPAR-γ activation [98] and preservation of cognitive performance through RvD1 formation [90]. 15-LOX has also detrimental effects as it is implicated in neurodegeneration and neurotoxicity through increase of oxidative stress [95–97].

Changes in SPM level and composition induced by the diet can have a great influence on the pro- and anti-inflammatory status of hippocampus and brain cells and reinforce the recommendation of n-3 PUFA-rich diet.

### **4. Conclusion**

These data highlight that n-3 LC-PUFA and their bioactive lipid derivatives are important regulators of neuroinflammation. SPMs are promising therapeutic compounds: they are of natural origin and act in physiologic dose ranges (nanomolar) as compared to EPA and DHA that act at micromolar ranges, and this confers the main advantage to use SPMs. Both brain n-3 LC-PUFA and SPMs are modulated by the diet in the brain and in brain cells confirming the notable role of nutrition in the regulation of inflammation. Alteration in dietary n-3 PUFAs should have dramatic consequences in brain and brain cell PUFA metabolism and finally in the response to neuroinflammation. The use of SPMs to treat neuroinflammation is still in emergence since some data are missing such as the affinity and function of SPM receptors. This field has to be completed. The instability of SPMs may be bypassed by the use of SPM analogues or by their encapsulation. The clinical form and the way of administration should also be defined.

#### **Acknowledgements**

Corinne Joffre was sponsored by the Fondation de France and the Fondation pour la Recherche Médicale.

**23**

**Author details**

Corinne Joffre1,2

1 INRA, Nutrition et Neurobiologie Intégrée, UMR 1286, Bordeaux, France

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

2 Université de Bordeaux 2, Bordeaux Cedex, France

\*Address all correspondence to: corinne.joffre@inra.fr

provided the original work is properly cited.

*Polyunsaturated Fatty Acid Metabolism in the Brain and Brain Cells*

*DOI: http://dx.doi.org/10.5772/intechopen.88232*

*Polyunsaturated Fatty Acid Metabolism in the Brain and Brain Cells DOI: http://dx.doi.org/10.5772/intechopen.88232*

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

**3.3 Nutrition as a factor of variation of SPM levels**

macrophages [177, 178] and microglia [179–181].

through increase of oxidative stress [95–97].

way of administration should also be defined.

**Acknowledgements**

pour la Recherche Médicale.

**4. Conclusion**

and reinforce the recommendation of n-3 PUFA-rich diet.

effect on microglia.

All these studies point out the central role of n-3 LC-PUFA and their bioactive mediators in the regulation of inflammation in the brain, especially through their

The level of these lipid derivatives is modulated by the diet. Indeed, we recently

show that a dietary n-3 LC-PUFA supplementation induces an n-3 LC-PUFA enrichment in the hippocampus associated with an increase in n-3 PUFA-derived SPMs and a decrease in n-6 PUFA-derived SPMs [69]. Our results confirm previous ones reporting that oral administration of EPA and DHA results in the generation of EPA-and DHA-derived mediators in the cortex of aged rats [168] and in the downregulation of the production of n-6 PUFA-derived mediators [169, 170]. The cellular origin of these bioactive lipid derivatives is still unknown. As described in the paragraph above, we know that dietary PUFA supplementation affects PUFA composition in brain cells that potentially could impact brain cell PUFA lipid derivatives. In response to LPS, n-3 LC-PUFA-supplemented mice display an anti-inflammatory SPM profile whereas n-3 LC-PUFA-deficient mice exhibit a pro-inflammatory SPM profile [69]. These results corroborate previous ones *in vivo* [171–176] and *in vitro* in

The level of SPMs is also dependent on the regulation of their biosynthesis enzymes. 15-LOX mRNA expression increases in n-3 LC-PUFA supplemented group and decreases in n-3 LC-PUFA deficient diet [27, 69, 182]. 15-LOX has beneficial properties such as neuroprotective properties *via* PPAR-γ activation [98] and preservation of cognitive performance through RvD1 formation [90]. 15-LOX has also detrimental effects as it is implicated in neurodegeneration and neurotoxicity

Changes in SPM level and composition induced by the diet can have a great influence on the pro- and anti-inflammatory status of hippocampus and brain cells

These data highlight that n-3 LC-PUFA and their bioactive lipid derivatives are important regulators of neuroinflammation. SPMs are promising therapeutic compounds: they are of natural origin and act in physiologic dose ranges (nanomolar) as compared to EPA and DHA that act at micromolar ranges, and this confers the main advantage to use SPMs. Both brain n-3 LC-PUFA and SPMs are modulated by the diet in the brain and in brain cells confirming the notable role of nutrition in the regulation of inflammation. Alteration in dietary n-3 PUFAs should have dramatic consequences in brain and brain cell PUFA metabolism and finally in the response to neuroinflammation. The use of SPMs to treat neuroinflammation is still in emergence since some data are missing such as the affinity and function of SPM receptors. This field has to be completed. The instability of SPMs may be bypassed by the use of SPM analogues or by their encapsulation. The clinical form and the

Corinne Joffre was sponsored by the Fondation de France and the Fondation

**22**

## **Author details**

Corinne Joffre1,2

1 INRA, Nutrition et Neurobiologie Intégrée, UMR 1286, Bordeaux, France

2 Université de Bordeaux 2, Bordeaux Cedex, France

\*Address all correspondence to: corinne.joffre@inra.fr

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

[1] Bazinet RP, Layé S. Polyunsaturated fatty acids and their metabolites in brain function and disease. Nature Reviews. Neuroscience. Dec. 2014;**15**(12):771-785

[2] Kidd PM. Omega-3 DHA and EPA for cognition, behavior, and mood: Clinical findings and structural-functional synergies with cell membrane phospholipids. Alternative Medicine Review. Sep. 2007;**12**(3):207-227

[3] Plourde M, Cunnane SC. Extremely limited synthesis of long chain polyunsaturates in adults: Implications for their dietary essentiality and use as supplements. Applied Physiology, Nutrition, and Metabolism. Aug. 2007;**32**(4):619-634

[4] Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: When the immune system subjugates the brain. Nature Reviews. Neuroscience. Jan. 2008;**9**(1):46-56

[5] Calder PC. Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance. Biochimica et Biophysica Acta. Apr. 2015;**1851**(4):469-484

[6] Serhan CN, Clish CB, Brannon J, Colgan SP, Chiang N, Gronert K. Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing. The Journal of Experimental Medicine. Oct. 2000;**192**(8):1197-1204

[7] Serhan CN. The resolution of inflammation: The devil in the flask and in the details. The FASEB Journal. May 2011;**25**(5):1441-1448

[8] Serhan CN. Pro-resolving lipid mediators are leads for

resolution physiology. Nature. Jun. 2014;**510**(7503):92-101

[9] Spite M, Serhan CN. Novel lipid mediators promote resolution of acute inflammation: Impact of aspirin and statins. Circulation Research. Nov. 2010;**107**(10):1170-1184

[10] Simopoulos AP. Evolutionary aspects of diet: The omega-6/omega-3 ratio and the brain. Molecular Neurobiology. Oct. 2011;**44**(2):203-215

[11] Sprecher H. Metabolism of highly unsaturated n-3 and n-6 fatty acids. Biochimica et Biophysica Acta. Jul. 2000;**1486**(2-3):219-231

[12] Joffre C et al. Modulation of brain PUFA content in different experimental models of mice. Prostaglandins, Leukotrienes, and Essential Fatty Acids. 2016;**114**:1-10

[13] Kitajka K et al. Effects of dietary omega-3 polyunsaturated fatty acids on brain gene expression. Proceedings of the National Academy of Sciences of the United States of America. Jul. 2004;**101**(30):10931-10936

[14] Chen CT, Bazinet RP. beta-oxidation and rapid metabolism, but not uptake regulate brain eicosapentaenoic acid levels. Prostaglandins, Leukotrienes, and Essential Fatty Acids. Jan. 2015;**92**:33-40

[15] Green JT, Liu Z, Bazinet RP. Brain phospholipid arachidonic acid half-lives are not altered following 15 weeks of N-3 polyunsaturated fatty acid adequate or deprived diet. Journal of Lipid Research. Mar. 2010;**51**(3):535-543

[16] Orsavova J, Misurcova L, Ambrozova JV, Vicha R, Mlcek J. Fatty acids composition of vegetable oils and its contribution to dietary energy intake and dependence of cardiovascular

**25**

*Polyunsaturated Fatty Acid Metabolism in the Brain and Brain Cells*

of omega-3 polyunsaturated fatty acids in human plasma lipid pools. Prostaglandins, Leukotrienes, and Essential Fatty Acids. May

[25] Simopoulos AP. The importance of the ratio of omega-6/omega-3 essential fatty acids. Biomedicine & Pharmacotherapy. Oct. 2002;**56**(8):365-379

[26] Igarashi M, Ma K, Chang L, Bell JM,

Rapoport SI. Dietary n-3 PUFA deprivation for 15 weeks upregulates elongase and desaturase expression in rat liver but not brain. Journal of Lipid Research. Nov. 2007;**48**(11):2463-2470

[27] Rao JS, Ertley RN, DeMar JC, Rapoport SI, Bazinet RP, Lee H-J. Dietary n-3 PUFA deprivation alters expression of enzymes of the arachidonic and docosahexaenoic acid cascades in rat frontal cortex. Molecular Psychiatry. Feb. 2007;**12**(2):151-157

[28] DeMar JC Jr, Ma K, Bell JM, Rapoport SI. Half-lives of

docosahexaenoic acid in rat brain phospholipids are prolonged by 15 weeks of nutritional deprivation of n-3 polyunsaturated fatty acids. Journal of Neurochemistry. Dec.

2004;**91**(5):1125-1137

Aug. 2014;**13**:137

[29] Salem N, Kuratko CN. A

and Disease. Sep. 2015;**14**:99

[31] Carrie I, Clement M, de Javel D, Frances H, Bourre JM. Specific phospholipid fatty acid composition

reexamination of krill oil bioavailability studies. Lipids in Health and Disease.

[30] Yurko-Mauro K, Kralovec J, Bailey-Hall E, Smeberg V, Stark JG, Salem N. Similar eicosapentaenoic acid and docosahexaenoic acid plasma levels achieved with fish oil or krill oil in a randomized double-blind four-week bioavailability study. Lipids in Health

2014;**90**(5):151-157

*DOI: http://dx.doi.org/10.5772/intechopen.88232*

[17] Lewinska A, Zebrowski J, Duda M, Gorka A, Wnuk M. Fatty acid profile and biological activities of linseed and rapeseed oils. Molecules. Dec.

2015;**20**(12):22872-22880

of omega-6 and omega-3

2003;**38**(4):391-398

1998;**33**(12):1151-1157

2012;**11**:144

[18] Meyer BJ, Mann NJ, Lewis JL, Milligan GC, Sinclair AJ, Howe PRC. Dietary intakes and food sources

[19] Taber L, Chiu CH, Whelan J. Assessment of the arachidonic acid content in foods commonly consumed in the American diet. Lipids. Dec.

[20] Strobel C, Jahreis G, Kuhnt K. Survey of n-3 and n-6 polyunsaturated fatty acids in fish and fish products. Lipids in Health and Disease. Oct.

[21] Burdge G. Alpha-linolenic acid metabolism in men and women:

Nutrition and Metabolic Care. Mar.

[22] Lucas M, Asselin G, Mérette C, Poulin M-J, Dodin S. Validation of an FFQ for evaluation of EPA and DHA intake. Public Health Nutrition. Oct.

[23] Blanchard H, Pédrono F, Boulier-Monthéan N, Catheline D, Rioux V, Legrand P. Comparative effects of wellbalanced diets enriched in α-linolenic or linoleic acids on LC-PUFA metabolism

Leukotrienes, and Essential Fatty Acids.

[24] Taha AY et al. Dietary omega-6 fatty acid lowering increases bioavailability

in rat tissues. Prostaglandins,

May 2013;**88**(5):383-389

Current Opinion in Clinical

2004;**7**(2):137-144

2009;**12**(10):1783-1790

Nutritional and biological implications.

polyunsaturated fatty acids. Lipids. Apr.

mortality on dietary intake of fatty acids. International Journal of Molecular Sciences. Jun. 2015;**16**(6):12871-12890

*Polyunsaturated Fatty Acid Metabolism in the Brain and Brain Cells DOI: http://dx.doi.org/10.5772/intechopen.88232*

mortality on dietary intake of fatty acids. International Journal of Molecular Sciences. Jun. 2015;**16**(6):12871-12890

[17] Lewinska A, Zebrowski J, Duda M, Gorka A, Wnuk M. Fatty acid profile and biological activities of linseed and rapeseed oils. Molecules. Dec. 2015;**20**(12):22872-22880

[18] Meyer BJ, Mann NJ, Lewis JL, Milligan GC, Sinclair AJ, Howe PRC. Dietary intakes and food sources of omega-6 and omega-3 polyunsaturated fatty acids. Lipids. Apr. 2003;**38**(4):391-398

[19] Taber L, Chiu CH, Whelan J. Assessment of the arachidonic acid content in foods commonly consumed in the American diet. Lipids. Dec. 1998;**33**(12):1151-1157

[20] Strobel C, Jahreis G, Kuhnt K. Survey of n-3 and n-6 polyunsaturated fatty acids in fish and fish products. Lipids in Health and Disease. Oct. 2012;**11**:144

[21] Burdge G. Alpha-linolenic acid metabolism in men and women: Nutritional and biological implications. Current Opinion in Clinical Nutrition and Metabolic Care. Mar. 2004;**7**(2):137-144

[22] Lucas M, Asselin G, Mérette C, Poulin M-J, Dodin S. Validation of an FFQ for evaluation of EPA and DHA intake. Public Health Nutrition. Oct. 2009;**12**(10):1783-1790

[23] Blanchard H, Pédrono F, Boulier-Monthéan N, Catheline D, Rioux V, Legrand P. Comparative effects of wellbalanced diets enriched in α-linolenic or linoleic acids on LC-PUFA metabolism in rat tissues. Prostaglandins, Leukotrienes, and Essential Fatty Acids. May 2013;**88**(5):383-389

[24] Taha AY et al. Dietary omega-6 fatty acid lowering increases bioavailability

of omega-3 polyunsaturated fatty acids in human plasma lipid pools. Prostaglandins, Leukotrienes, and Essential Fatty Acids. May 2014;**90**(5):151-157

[25] Simopoulos AP. The importance of the ratio of omega-6/omega-3 essential fatty acids. Biomedicine & Pharmacotherapy. Oct. 2002;**56**(8):365-379

[26] Igarashi M, Ma K, Chang L, Bell JM, Rapoport SI. Dietary n-3 PUFA deprivation for 15 weeks upregulates elongase and desaturase expression in rat liver but not brain. Journal of Lipid Research. Nov. 2007;**48**(11):2463-2470

[27] Rao JS, Ertley RN, DeMar JC, Rapoport SI, Bazinet RP, Lee H-J. Dietary n-3 PUFA deprivation alters expression of enzymes of the arachidonic and docosahexaenoic acid cascades in rat frontal cortex. Molecular Psychiatry. Feb. 2007;**12**(2):151-157

[28] DeMar JC Jr, Ma K, Bell JM, Rapoport SI. Half-lives of docosahexaenoic acid in rat brain phospholipids are prolonged by 15 weeks of nutritional deprivation of n-3 polyunsaturated fatty acids. Journal of Neurochemistry. Dec. 2004;**91**(5):1125-1137

[29] Salem N, Kuratko CN. A reexamination of krill oil bioavailability studies. Lipids in Health and Disease. Aug. 2014;**13**:137

[30] Yurko-Mauro K, Kralovec J, Bailey-Hall E, Smeberg V, Stark JG, Salem N. Similar eicosapentaenoic acid and docosahexaenoic acid plasma levels achieved with fish oil or krill oil in a randomized double-blind four-week bioavailability study. Lipids in Health and Disease. Sep. 2015;**14**:99

[31] Carrie I, Clement M, de Javel D, Frances H, Bourre JM. Specific phospholipid fatty acid composition

**24**

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

resolution physiology. Nature. Jun.

[9] Spite M, Serhan CN. Novel lipid mediators promote resolution of acute inflammation: Impact of aspirin and statins. Circulation Research. Nov.

[10] Simopoulos AP. Evolutionary aspects of diet: The omega-6/omega-3

Neurobiology. Oct. 2011;**44**(2):203-215

[11] Sprecher H. Metabolism of highly unsaturated n-3 and n-6 fatty acids. Biochimica et Biophysica Acta. Jul.

[12] Joffre C et al. Modulation of brain PUFA content in different experimental

Leukotrienes, and Essential Fatty Acids.

[14] Chen CT, Bazinet RP. beta-oxidation and rapid metabolism, but not uptake regulate brain eicosapentaenoic acid levels. Prostaglandins, Leukotrienes, and Essential Fatty Acids. Jan.

[15] Green JT, Liu Z, Bazinet RP. Brain phospholipid arachidonic acid half-lives are not altered following 15 weeks of N-3 polyunsaturated fatty acid adequate or deprived diet. Journal of Lipid Research. Mar. 2010;**51**(3):535-543

Ambrozova JV, Vicha R, Mlcek J. Fatty acids composition of vegetable oils and its contribution to dietary energy intake and dependence of cardiovascular

[16] Orsavova J, Misurcova L,

[13] Kitajka K et al. Effects of dietary omega-3 polyunsaturated fatty acids on brain gene expression. Proceedings of the National Academy of Sciences of the United States of America. Jul.

2004;**101**(30):10931-10936

models of mice. Prostaglandins,

ratio and the brain. Molecular

2014;**510**(7503):92-101

2010;**107**(10):1170-1184

2000;**1486**(2-3):219-231

2016;**114**:1-10

2015;**92**:33-40

[1] Bazinet RP, Layé S. Polyunsaturated fatty acids and their metabolites in brain function and disease. Nature Reviews. Neuroscience. Dec. 2014;**15**(12):771-785

**References**

[2] Kidd PM. Omega-3 DHA and EPA for cognition, behavior, and mood: Clinical findings and structural-functional synergies with cell membrane phospholipids. Alternative Medicine Review. Sep. 2007;**12**(3):207-227

[3] Plourde M, Cunnane SC. Extremely

polyunsaturates in adults: Implications for their dietary essentiality and use as supplements. Applied Physiology, Nutrition, and Metabolism. Aug.

[4] Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and

depression: When the immune system subjugates the brain. Nature Reviews. Neuroscience. Jan. 2008;**9**(1):46-56

[5] Calder PC. Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance. Biochimica et Biophysica Acta. Apr. 2015;**1851**(4):469-484

[6] Serhan CN, Clish CB, Brannon J, Colgan SP, Chiang N, Gronert K. Novel

functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing. The Journal of Experimental Medicine. Oct.

[7] Serhan CN. The resolution of

[8] Serhan CN. Pro-resolving lipid mediators are leads for

inflammation: The devil in the flask and in the details. The FASEB Journal. May

2000;**192**(8):1197-1204

2011;**25**(5):1441-1448

limited synthesis of long chain

2007;**32**(4):619-634

of brain regions in mice. Effects of n-3 polyunsaturated fatty acid deficiency and phospholipid supplementation. Journal of Lipid Research. Mar. 2000;**41**(3):465-472

[32] Chung WL, Chen JJ, Su HM. Fish oil supplementation of control and (n-3) fatty acid-deficient male rats enhances reference and working memory performance and increases brain regional docosahexaenoic acid levels. The Journal of Nutrition. Jun. 2008;**138**(6):1165-1171

[33] Little SJ, Lynch MA, Manku M, Nicolaou A. Docosahexaenoic acidinduced changes in phospholipids in cortex of young and aged rats: A lipidomic analysis. Prostaglandins, Leukotrienes, and Essential Fatty Acids. Oct. 2007;**77**(3-4):155-162

[34] McNamara RK, Carlson SE. Role of omega-3 fatty acids in brain development and function: Potential implications for the pathogenesis and prevention of psychopathology. Prostaglandins, Leukotrienes, and Essential Fatty Acids. Oct. 2006;**75**(4-5):329-349

[35] Xiao Y, Huang Y, Chen ZY. Distribution, depletion and recovery of docosahexaenoic acid are region-specific in rat brain. The British Journal of Nutrition. Oct. 2005;**94**(4):544-550

[36] Clandinin MT, Chappell JE, Leong S, Heim T, Swyer PR, Chance GW. Extrauterine fatty acid accretion in infant brain: Implications for fatty acid requirements. Early Human Development. Jun. 1980;**4**(2):131-138

[37] Clandinin MT, Chappell JE, Leong S, Heim T, Swyer PR, Chance GW. Intrauterine fatty acid accretion rates in human brain: Implications for fatty acid requirements. Early Human Development. Jun. 1980;**4**(2):121-129

[38] Green P, Glozman S, Kamensky B, Yavin E. Developmental changes in rat brain membrane lipids and fatty acids. The preferential prenatal accumulation of docosahexaenoic acid. Journal of Lipid Research. May 1999;**40**(5):960-966

[39] Giedd JN et al. Brain development during childhood and adolescence: A longitudinal MRI study. Nature Neuroscience. Oct. 1999;**2**(10):861-863

[40] Morgane PJ et al. Prenatal malnutrition and development of the brain. Neuroscience and Biobehavioral Reviews. Spring 1993;**17**(1):91-128

[41] Delion S, Chalon S, Hérault J, Guilloteau D, Besnard JC, Durand G. Chronic dietary alpha-linolenic acid deficiency alters dopaminergic and serotoninergic neurotransmission in rats. The Journal of Nutrition. Dec. 1994;**124**(12):2466-2476

[42] McNamara RK, Able J, Jandacek R, Rider T, Tso P. Inbred C57BL/6J and DBA/2J mouse strains exhibit constitutive differences in regional brain fatty acid composition. Lipids. Jan. 2009;**44**(1):1-8

[43] Moriguchi T, Loewke J, Garrison M, Catalan JN, Salem N Jr. Reversal of docosahexaenoic acid deficiency in the rat brain, retina, liver, and serum. Journal of Lipid Research. Mar. 2001;**42**(3):419-427

[44] Hamazaki K, Maekawa M, Toyota T, Dean B, Hamazaki T, Yoshikawa T. Fatty acid composition of the postmortem prefrontal cortex of patients with schizophrenia, bipolar disorder, and major depressive disorder. Psychiatry Research. Jun. 2015;**227**(2-3):353-359

[45] Renaud J, Therien HM, Plouffe M, Martinoli MG. Neuroinflammation: Dr Jekyll or Mr Hyde? Medical Science (Paris). Nov. 2015;**31**(11):979-988

**27**

*Polyunsaturated Fatty Acid Metabolism in the Brain and Brain Cells*

[53] Calder PC. Immunomodulation by omega-3 fatty acids. Prostaglandins, Leukotrienes, and Essential Fatty Acids.

[54] Alashmali SM, Hopperton KE, Bazinet RP. Lowering dietary n-6 polyunsaturated fatty acids: Interaction with brain arachidonic and docosahexaenoic acids. Current Opinion in Lipidology. Feb. 2016;**27**(1):54-66

[55] Connor WE, Neuringer M, Lin DS. Dietary effects on brain fatty acid composition: The reversibility of n-3 fatty acid deficiency and turnover of docosahexaenoic acid in the brain, erythrocytes, and plasma of rhesus monkeys. Journal of Lipid Research.

[56] Larrieu T, Madore C, Joffre C, Layé S. Nutritional n-3 polyunsaturated fatty acids deficiency alters cannabinoid receptor signaling pathway in the brain and associated anxiety-like behavior in mice. Journal of Physiology and Biochemistry. Dec. 2012;**68**(4):671-681

Dec. 2007;**77**(5-6):327-335

Feb. 1990;**31**(2):237-247

[57] Delpech J-C et al. Dietary n-3 PUFAs deficiency increases vulnerability to inflammationinduced spatial memory impairment. Neuropsychopharmacology. Nov.

[58] Manduca A et al. Amplification of mGlu5-endocannabinoid signaling rescues behavioral and synaptic deficits in a mouse model of adolescent and adult dietary polyunsaturated fatty acid imbalance. Journal of Neuroscience;**37**(29):6851-6868

[59] Broadhurst CL, Wang Y, Crawford MA, Cunnane SC, Parkington JE, Schmidt WF. Brain-specific lipids from marine, lacustrine, or terrestrial food resources: Potential impact on early African *Homo sapiens*. Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology. Apr.

2015;**40**(12):2774-2787

2002;**131**(4):653-673

*DOI: http://dx.doi.org/10.5772/intechopen.88232*

composition of rat brain cells (neurons, astrocytes, and oligodendrocytes) and of subcellular fractions (myelin and synaptosomes) induced by a diet devoid of n-3 fatty acids. Journal of Neurochemistry. Aug.

1984;**43**(2):342-348

1981;**3**(5):329-334

2018;**133**:1-7

[47] Cohen SR, Bernsohn J.

Incorporation of 1-14C labeled fatty acids into isolated neuronal soma, astroglia and oligodendroglia from calf brain. Brain Research;**60**(2):521-525

[48] Morand O, Masson M, Baumann N, Bourre JM. Exogenous [1-14C]lignoceric acid uptake by neurons, astrocytes and myelin, as compared to incorporation of [1-14C]palmitic and stearic acids. Neurochemistry International.

[49] Morand O et al. Alteration in fatty acid composition of neurons, astrocytes, oligodendrocytes, myelin and synaptosomes in intrauterine malnutrition in rat. Annals of Nutrition & Metabolism. 1982;**26**(2):111-120

[50] Rey C et al. Maternal n-3 polyunsaturated fatty acid dietary supply modulates microglia lipid

content in the offspring. Prostaglandins, Leukotrienes, and Essential Fatty Acids.

[51] Madore C et al. Nutritional n-3 PUFAs deficiency during perinatal periods alters brain innate immune system and neuronal plasticityassociated genes. Brain, Behavior, and

[52] Chen CT, Liu Z, Ouellet M, Calon F, Bazinet RP. Rapid beta-oxidation of eicosapentaenoic acid in mouse brain: An in situ study. Prostaglandins, Leukotrienes, and Essential Fatty Acids.

Immunity. Oct. 2014;**41**:22-31

Feb. 2009;**80**(2-3):157-163

[46] Bourre JM, Pascal G, Durand G, Masson M, Dumont O, Piciotti M. Alterations in the fatty acid

*Polyunsaturated Fatty Acid Metabolism in the Brain and Brain Cells DOI: http://dx.doi.org/10.5772/intechopen.88232*

[46] Bourre JM, Pascal G, Durand G, Masson M, Dumont O, Piciotti M. Alterations in the fatty acid composition of rat brain cells (neurons, astrocytes, and oligodendrocytes) and of subcellular fractions (myelin and synaptosomes) induced by a diet devoid of n-3 fatty acids. Journal of Neurochemistry. Aug. 1984;**43**(2):342-348

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

[38] Green P, Glozman S, Kamensky B, Yavin E. Developmental changes in rat brain membrane lipids and fatty acids. The preferential prenatal accumulation of docosahexaenoic acid. Journal of Lipid Research. May

[39] Giedd JN et al. Brain development during childhood and adolescence: A longitudinal MRI study. Nature Neuroscience. Oct. 1999;**2**(10):861-863

[40] Morgane PJ et al. Prenatal malnutrition and development of the brain. Neuroscience and Biobehavioral Reviews. Spring 1993;**17**(1):91-128

[41] Delion S, Chalon S, Hérault J, Guilloteau D, Besnard JC, Durand G. Chronic dietary alpha-linolenic acid deficiency alters dopaminergic and serotoninergic neurotransmission in rats. The Journal of Nutrition. Dec.

[42] McNamara RK, Able J, Jandacek R,

[43] Moriguchi T, Loewke J, Garrison M, Catalan JN, Salem N Jr. Reversal of docosahexaenoic acid deficiency in the rat brain, retina, liver, and serum. Journal of Lipid Research. Mar.

[44] Hamazaki K, Maekawa M, Toyota T, Dean B, Hamazaki T, Yoshikawa T. Fatty acid composition of the postmortem prefrontal cortex of patients with schizophrenia, bipolar disorder, and major depressive disorder. Psychiatry Research. Jun. 2015;**227**(2-3):353-359

[45] Renaud J, Therien HM, Plouffe M, Martinoli MG. Neuroinflammation: Dr Jekyll or Mr Hyde? Medical Science (Paris). Nov. 2015;**31**(11):979-988

Rider T, Tso P. Inbred C57BL/6J and DBA/2J mouse strains exhibit constitutive differences in regional brain fatty acid composition. Lipids.

1994;**124**(12):2466-2476

Jan. 2009;**44**(1):1-8

2001;**42**(3):419-427

1999;**40**(5):960-966

of brain regions in mice. Effects of n-3 polyunsaturated fatty acid deficiency and phospholipid supplementation. Journal of Lipid Research. Mar.

[32] Chung WL, Chen JJ, Su HM. Fish oil supplementation of control and (n-3) fatty acid-deficient male rats enhances reference and working memory performance and increases brain regional docosahexaenoic acid levels. The Journal of Nutrition. Jun.

[33] Little SJ, Lynch MA, Manku M, Nicolaou A. Docosahexaenoic acidinduced changes in phospholipids in cortex of young and aged rats: A lipidomic analysis. Prostaglandins, Leukotrienes, and Essential Fatty Acids.

[34] McNamara RK, Carlson SE. Role of omega-3 fatty acids in brain development and function: Potential implications for the pathogenesis and prevention of psychopathology. Prostaglandins, Leukotrienes, and Essential Fatty Acids. Oct.

2000;**41**(3):465-472

2008;**138**(6):1165-1171

Oct. 2007;**77**(3-4):155-162

2006;**75**(4-5):329-349

2005;**94**(4):544-550

[35] Xiao Y, Huang Y, Chen ZY. Distribution, depletion and recovery of docosahexaenoic acid are region-specific in rat brain. The British Journal of Nutrition. Oct.

[36] Clandinin MT, Chappell JE, Leong S, Heim T, Swyer PR, Chance GW. Extrauterine fatty acid accretion in infant brain: Implications for fatty acid requirements. Early Human Development. Jun. 1980;**4**(2):131-138

[37] Clandinin MT, Chappell JE, Leong S, Heim T, Swyer PR, Chance GW. Intrauterine fatty acid accretion rates in human brain: Implications for fatty acid requirements. Early Human Development. Jun. 1980;**4**(2):121-129

**26**

[47] Cohen SR, Bernsohn J. Incorporation of 1-14C labeled fatty acids into isolated neuronal soma, astroglia and oligodendroglia from calf brain. Brain Research;**60**(2):521-525

[48] Morand O, Masson M, Baumann N, Bourre JM. Exogenous [1-14C]lignoceric acid uptake by neurons, astrocytes and myelin, as compared to incorporation of [1-14C]palmitic and stearic acids. Neurochemistry International. 1981;**3**(5):329-334

[49] Morand O et al. Alteration in fatty acid composition of neurons, astrocytes, oligodendrocytes, myelin and synaptosomes in intrauterine malnutrition in rat. Annals of Nutrition & Metabolism. 1982;**26**(2):111-120

[50] Rey C et al. Maternal n-3 polyunsaturated fatty acid dietary supply modulates microglia lipid content in the offspring. Prostaglandins, Leukotrienes, and Essential Fatty Acids. 2018;**133**:1-7

[51] Madore C et al. Nutritional n-3 PUFAs deficiency during perinatal periods alters brain innate immune system and neuronal plasticityassociated genes. Brain, Behavior, and Immunity. Oct. 2014;**41**:22-31

[52] Chen CT, Liu Z, Ouellet M, Calon F, Bazinet RP. Rapid beta-oxidation of eicosapentaenoic acid in mouse brain: An in situ study. Prostaglandins, Leukotrienes, and Essential Fatty Acids. Feb. 2009;**80**(2-3):157-163

[53] Calder PC. Immunomodulation by omega-3 fatty acids. Prostaglandins, Leukotrienes, and Essential Fatty Acids. Dec. 2007;**77**(5-6):327-335

[54] Alashmali SM, Hopperton KE, Bazinet RP. Lowering dietary n-6 polyunsaturated fatty acids: Interaction with brain arachidonic and docosahexaenoic acids. Current Opinion in Lipidology. Feb. 2016;**27**(1):54-66

[55] Connor WE, Neuringer M, Lin DS. Dietary effects on brain fatty acid composition: The reversibility of n-3 fatty acid deficiency and turnover of docosahexaenoic acid in the brain, erythrocytes, and plasma of rhesus monkeys. Journal of Lipid Research. Feb. 1990;**31**(2):237-247

[56] Larrieu T, Madore C, Joffre C, Layé S. Nutritional n-3 polyunsaturated fatty acids deficiency alters cannabinoid receptor signaling pathway in the brain and associated anxiety-like behavior in mice. Journal of Physiology and Biochemistry. Dec. 2012;**68**(4):671-681

[57] Delpech J-C et al. Dietary n-3 PUFAs deficiency increases vulnerability to inflammationinduced spatial memory impairment. Neuropsychopharmacology. Nov. 2015;**40**(12):2774-2787

[58] Manduca A et al. Amplification of mGlu5-endocannabinoid signaling rescues behavioral and synaptic deficits in a mouse model of adolescent and adult dietary polyunsaturated fatty acid imbalance. Journal of Neuroscience;**37**(29):6851-6868

[59] Broadhurst CL, Wang Y, Crawford MA, Cunnane SC, Parkington JE, Schmidt WF. Brain-specific lipids from marine, lacustrine, or terrestrial food resources: Potential impact on early African *Homo sapiens*. Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology. Apr. 2002;**131**(4):653-673

[60] Crawford MA et al. Evidence for the unique function of docosahexaenoic acid during the evolution of the modern hominid brain. Lipids. 1999;**34**(Suppl):S39-S47

[61] Rapoport SI, Rao JS, Igarashi M. Brain metabolism of nutritionally essential polyunsaturated fatty acids depends on both the diet and the liver. Prostaglandins, Leukotrienes, and Essential Fatty Acids. Nov. 2007;**77**(5-6):251-261

[62] Cho HP, Nakamura MT, Clarke SD. Cloning, expression, and nutritional regulation of the mammalian Delta-6 desaturase. The Journal of Biological Chemistry. Jan. 1999;**274**(1):471-477

[63] Wang Y, Botolin D, Christian B, Busik J, Xu J, Jump DB. Tissue-specific, nutritional, and developmental regulation of rat fatty acid elongases. Journal of Lipid Research. Apr. 2005;**46**(4):706-715

[64] de Theije CG et al. Dietary long chain n-3 polyunsaturated fatty acids prevent impaired social behaviour and normalize brain dopamine levels in food allergic mice. Neuropharmacology. Mar. 2015;**90**:15-22

[65] Hiratsuka S, Koizumi K, Ooba T, Yokogoshi H. Effects of dietary docosahexaenoic acid connecting phospholipids on the learning ability and fatty acid composition of the brain. Journal of Nutritional Science and Vitaminology (Tokyo). Aug. 2009;**55**(4):374-380

[66] Kitson AP et al. Effect of dietary docosahexaenoic acid (DHA) in phospholipids or triglycerides on brain DHA uptake and accretion. The Journal of Nutritional Biochemistry. Jul. 2016;**33**:91-102

[67] Skorve J et al. Fish oil and krill oil differentially modify the liver and brain lipidome when fed to mice. Lipids in Health and Disease. Aug. 2015;**14**:88

[68] Lacombe RJS, Giuliano V, Colombo SM, Arts MT, Bazinet RP. Compoundspecific isotope analysis resolves the dietary origin of docosahexaenoic acid in the mouse brain. Journal of Lipid Research. Oct. 2017;**58**(10):2071-2081

[69] Rey C et al. Dietary n-3 long chain PUFA supplementation promotes a proresolving oxylipin profile in the brain. Brain, Behavior, and Immunity. Feb. 2019;**76**:17-27

[70] Orr SK et al. Unesterified docosahexaenoic acid is protective in neuroinflammation. Journal of Neurochemistry. Nov. 2013;**127**(3):378-393

[71] Bascoul-Colombo C, Guschina IA, Maskrey BH, Good M, O'Donnell VB, Harwood JL. Dietary DHA supplementation causes selective changes in phospholipids from different brain regions in both wild type mice and the Tg2576 mouse model of Alzheimer's disease. Biochimica et Biophysica Acta. Jun. 2016;**1861**(6):524-537

[72] Labrousse VF et al. Short-term long chain omega3 diet protects from neuroinflammatory processes and memory impairment in aged mice. PLoS ONE. 2012;**7**(5):e36861

[73] Boudrault C, Bazinet RP, Kang JX, Ma DW. Cyclooxygenase-2 and n-6 PUFA are lower and DHA is higher in the cortex of fat-1 mice. Neurochemistry International. Mar. 2010;**56**(4):585-589

[74] Bousquet M et al. Transgenic conversion of omega-6 into omega-3 fatty acids in a mouse model of Parkinson's disease. Journal of Lipid Research. Feb. 2011;**52**(2):263-271

[75] He C, Qu X, Cui L, Wang J, Kang JX. Improved spatial learning

**29**

*Polyunsaturated Fatty Acid Metabolism in the Brain and Brain Cells*

phosphoinositide formation and chemotaxis in neutrophils. The Journal of Clinical Investigation. Feb.

[83] P. Needleman, A. Raz, M. S. Minkes, J. A. Ferrendelli, and H. Sprecher Triene prostaglandins: Prostacyclin and thromboxane biosynthesis and unique biological properties. Proceedings of the National Academy of Sciences of the United States of America, vol. 76, no. 2,

1993;**91**(2):651-660

pp. 944-948, Feb. 1979

1999;**29**(8):1129-1135

Aug. 2013;**72**(3):326-336

[84] Obata T, Nagakura T, Masaki T, Maekawa K, Yamashita

K. Eicosapentaenoic acid inhibits prostaglandin D2 generation by inhibiting cyclo-oxygenase-2 in cultured human mast cells.

Clinical and Experimental Allergy.

[85] Calder PC. n-3 fatty acids, inflammation and immunity: New mechanisms to explain old actions. The Proceedings of the Nutrition Society.

[86] Headland SE, Norling LV. The resolution of inflammation:

Principles and challenges. Seminars in Immunology. May 2015;**27**(3):149-160

[87] Serhan CN, Chiang N. Resolution phase lipid mediators of inflammation:

Agonists of resolution. Current Opinion in Pharmacology. Aug.

[88] Serhan CN et al. Resolvins: A family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals. The Journal of Experimental Medicine. Oct.

[89] Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: Dual anti-inflammatory and pro-resolution lipid mediators. Nature Reviews. Immunology. May 2008;**8**(5):349-361

2013;**13**(4):632-640

2002;**196**(8):1025-1037

*DOI: http://dx.doi.org/10.5772/intechopen.88232*

performance of fat-1 mice is associated with enhanced neurogenesis and

neuritogenesis by docosahexaenoic acid. Proceedings of the National Academy of Sciences of the United States of America. Jul. 2009;**106**(27):11370-11375

[76] Orr SK, Tong JY, Kang JX, Ma DW, Bazinet RP. The fat-1 mouse has brain docosahexaenoic acid levels achievable through fish oil feeding. Neurochemical Research. May 2010;**35**(5):811-819

[77] Delpech J-C et al. Transgenic increase in n-3/n-6 fatty acid ratio protects against cognitive deficits induced by an immune challenge

Neuropsychopharmacology. Feb.

2015;**40**(3):525-536

2005;**93**(5):601-611

through decrease of neuroinflammation.

[78] Bowen RA, Clandinin MT. Maternal dietary 22:6n-3 is more effective than 18nn:3n-3 in increasing the 22:6n-3 content in phospholipids of glial cells from neonatal rat brain. The British Journal of Nutrition. May

[79] Destaillats F et al. Differential effect of maternal diet supplementation with alpha-linolenic acid or n-3 long-chain polyunsaturated fatty acids on glial cell phosphatidylethanolamine and phosphatidylserine fatty acid profile in neonate rat brains. Nutrition & Metabolism (London). Jan. 2010;**7**:2

[80] Layé S. Polyunsaturated fatty acids, neuroinflammation and well being. Prostaglandins, Leukotrienes, and Essential Fatty Acids. Jun.

[81] Calder PC. Dietary modification of inflammation with lipids. The Proceedings of the Nutrition Society.

[82] Sperling RI, Benincaso AI, Knoell CT, Larkin JK, Austen KF, Robinson DR. Dietary omega-3 polyunsaturated fatty acids inhibit

2010;**82**(4-6):295-303

Aug. 2002;**61**(3):345-358

*Polyunsaturated Fatty Acid Metabolism in the Brain and Brain Cells DOI: http://dx.doi.org/10.5772/intechopen.88232*

performance of fat-1 mice is associated with enhanced neurogenesis and neuritogenesis by docosahexaenoic acid. Proceedings of the National Academy of Sciences of the United States of America. Jul. 2009;**106**(27):11370-11375

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

lipidome when fed to mice. Lipids in Health and Disease. Aug. 2015;**14**:88

[68] Lacombe RJS, Giuliano V, Colombo SM, Arts MT, Bazinet RP. Compoundspecific isotope analysis resolves the dietary origin of docosahexaenoic acid in the mouse brain. Journal of Lipid Research. Oct. 2017;**58**(10):2071-2081

[69] Rey C et al. Dietary n-3 long chain PUFA supplementation promotes a proresolving oxylipin profile in the brain. Brain, Behavior, and Immunity. Feb.

[70] Orr SK et al. Unesterified docosahexaenoic acid is protective in neuroinflammation. Journal of Neurochemistry. Nov. 2013;**127**(3):378-393

[71] Bascoul-Colombo C, Guschina IA, Maskrey BH, Good M, O'Donnell VB, Harwood JL. Dietary DHA supplementation causes selective changes in phospholipids from different brain regions in both wild type mice and the Tg2576 mouse model of Alzheimer's disease. Biochimica et Biophysica Acta.

[72] Labrousse VF et al. Short-term long chain omega3 diet protects from neuroinflammatory processes and memory impairment in aged mice. PLoS

[73] Boudrault C, Bazinet RP, Kang JX, Ma DW. Cyclooxygenase-2 and n-6 PUFA are lower and DHA is higher in the cortex of fat-1 mice. Neurochemistry International. Mar.

[74] Bousquet M et al. Transgenic conversion of omega-6 into omega-3 fatty acids in a mouse model of Parkinson's disease. Journal of Lipid Research. Feb. 2011;**52**(2):263-271

[75] He C, Qu X, Cui L, Wang J, Kang JX. Improved spatial learning

Jun. 2016;**1861**(6):524-537

ONE. 2012;**7**(5):e36861

2010;**56**(4):585-589

2019;**76**:17-27

[60] Crawford MA et al. Evidence for the unique function of docosahexaenoic

[61] Rapoport SI, Rao JS, Igarashi M. Brain metabolism of nutritionally essential polyunsaturated fatty acids depends on both the diet and the liver. Prostaglandins, Leukotrienes, and Essential Fatty Acids. Nov.

acid during the evolution of the modern hominid brain. Lipids. 1999;**34**(Suppl):S39-S47

2007;**77**(5-6):251-261

1999;**274**(1):471-477

2005;**46**(4):706-715

2015;**90**:15-22

2009;**55**(4):374-380

2016;**33**:91-102

[62] Cho HP, Nakamura MT, Clarke SD. Cloning, expression, and nutritional regulation of the mammalian Delta-6 desaturase. The Journal of Biological Chemistry. Jan.

[63] Wang Y, Botolin D, Christian B, Busik J, Xu J, Jump DB. Tissue-specific,

[64] de Theije CG et al. Dietary long chain n-3 polyunsaturated fatty acids prevent impaired social behaviour and normalize brain dopamine levels in food allergic mice. Neuropharmacology. Mar.

[65] Hiratsuka S, Koizumi K, Ooba T, Yokogoshi H. Effects of dietary docosahexaenoic acid connecting phospholipids on the learning ability and fatty acid composition of the brain. Journal of Nutritional Science and Vitaminology (Tokyo). Aug.

[66] Kitson AP et al. Effect of dietary docosahexaenoic acid (DHA) in phospholipids or triglycerides on brain DHA uptake and accretion. The Journal of Nutritional Biochemistry. Jul.

[67] Skorve J et al. Fish oil and krill oil differentially modify the liver and brain

nutritional, and developmental regulation of rat fatty acid elongases. Journal of Lipid Research. Apr.

**28**

[76] Orr SK, Tong JY, Kang JX, Ma DW, Bazinet RP. The fat-1 mouse has brain docosahexaenoic acid levels achievable through fish oil feeding. Neurochemical Research. May 2010;**35**(5):811-819

[77] Delpech J-C et al. Transgenic increase in n-3/n-6 fatty acid ratio protects against cognitive deficits induced by an immune challenge through decrease of neuroinflammation. Neuropsychopharmacology. Feb. 2015;**40**(3):525-536

[78] Bowen RA, Clandinin MT. Maternal dietary 22:6n-3 is more effective than 18nn:3n-3 in increasing the 22:6n-3 content in phospholipids of glial cells from neonatal rat brain. The British Journal of Nutrition. May 2005;**93**(5):601-611

[79] Destaillats F et al. Differential effect of maternal diet supplementation with alpha-linolenic acid or n-3 long-chain polyunsaturated fatty acids on glial cell phosphatidylethanolamine and phosphatidylserine fatty acid profile in neonate rat brains. Nutrition & Metabolism (London). Jan. 2010;**7**:2

[80] Layé S. Polyunsaturated fatty acids, neuroinflammation and well being. Prostaglandins, Leukotrienes, and Essential Fatty Acids. Jun. 2010;**82**(4-6):295-303

[81] Calder PC. Dietary modification of inflammation with lipids. The Proceedings of the Nutrition Society. Aug. 2002;**61**(3):345-358

[82] Sperling RI, Benincaso AI, Knoell CT, Larkin JK, Austen KF, Robinson DR. Dietary omega-3 polyunsaturated fatty acids inhibit phosphoinositide formation and chemotaxis in neutrophils. The Journal of Clinical Investigation. Feb. 1993;**91**(2):651-660

[83] P. Needleman, A. Raz, M. S. Minkes, J. A. Ferrendelli, and H. Sprecher Triene prostaglandins: Prostacyclin and thromboxane biosynthesis and unique biological properties. Proceedings of the National Academy of Sciences of the United States of America, vol. 76, no. 2, pp. 944-948, Feb. 1979

[84] Obata T, Nagakura T, Masaki T, Maekawa K, Yamashita K. Eicosapentaenoic acid inhibits prostaglandin D2 generation by inhibiting cyclo-oxygenase-2 in cultured human mast cells. Clinical and Experimental Allergy. 1999;**29**(8):1129-1135

[85] Calder PC. n-3 fatty acids, inflammation and immunity: New mechanisms to explain old actions. The Proceedings of the Nutrition Society. Aug. 2013;**72**(3):326-336

[86] Headland SE, Norling LV. The resolution of inflammation: Principles and challenges. Seminars in Immunology. May 2015;**27**(3):149-160

[87] Serhan CN, Chiang N. Resolution phase lipid mediators of inflammation: Agonists of resolution. Current Opinion in Pharmacology. Aug. 2013;**13**(4):632-640

[88] Serhan CN et al. Resolvins: A family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals. The Journal of Experimental Medicine. Oct. 2002;**196**(8):1025-1037

[89] Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: Dual anti-inflammatory and pro-resolution lipid mediators. Nature Reviews. Immunology. May 2008;**8**(5):349-361

[90] Shalini S-M et al. Distribution of Alox15 in the rat brain and its role in prefrontal cortical resolvin D1 formation and spatial working memory. Molecular Neurobiology. 2018;**55**(2):1537-1550

[91] Nadjar A et al. NFkappaB activates in vivo the synthesis of inducible Cox-2 in the brain. Journal of Cerebral Blood Flow and Metabolism. Aug. 2005;**25**(8):1047-1059

[92] Navarro-Mabarak C, Camacho-Carranza R, Espinosa-Aguirre JJ. Cytochrome P450 in the central nervous system as a therapeutic target in neurodegenerative diseases. Drug Metabolism Reviews. 2018;**50**(2):95-108

[93] Czapski GA, Gajkowska B, Strosznajder JB. Systemic administration of lipopolysaccharide induces molecular and morphological alterations in the hippocampus. Brain Research. Oct. 2010;**1356**:85-94

[94] Schwab JM, Chiang N, Arita M, Serhan CN. Resolvin E1 and protectin D1 activate inflammationresolution programmes. Nature. Jun. 2007;**447**(7146):869-874

[95] Pratico D et al. 12/15-lipoxygenase is increased in Alzheimer's disease: Possible involvement in brain oxidative stress. The American Journal of Pathology. May 2004;**164**(5):1655-1662

[96] Wang X et al. Resolution of inflammation is altered in Alzheimer's disease. Alzheimer's & Dementia. Jan. 2015;**11**(1):40-50 e1-2

[97] Yigitkanli K, Zheng Y, Pekcec A, Lo EH, van Leyen K. Increased 12/15-lipoxygenase leads to widespread brain injury following global cerebral ischemia. Translational Stroke Research. Apr. 2017;**8**(2):194-202

[98] Sun L, Xu YW, Han J, Liang H, Wang N, Cheng Y. 12/15-Lipoxygenase metabolites of arachidonic acid activate PPARgamma: A possible neuroprotective effect in ischemic brain. Journal of Lipid Research. Mar. 2015;**56**(3):502-514

[99] Bystrom J et al. Endogenous epoxygenases are modulators of monocyte/macrophage activity. PLoS One. 2011;**6**(10):e26591

[100] Fleming I. Cytochrome P450 dependent eicosanoid production and crosstalk. Current Opinion in Lipidology. Oct. 2011;**22**(5):403-409

[101] Gilroy DW et al. CYP450-derived oxylipins mediate inflammatory resolution. Proceedings of the National Academy of Sciences of the United States of America. Jun. 2016;**113**(23):E3240-E3249

[102] Nebert DW, Wikvall K, Miller WL. Human cytochromes P450 in health and disease. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 2013;**368**(1612):20120431

[103] Levi G, Minghetti L, Aloisi F. Regulation of prostanoid synthesis in microglial cells and effects of prostaglandin E2 on microglial functions. Biochimie. Nov. 1998;**80**(11):899-904

[104] Farooqui AA, Horrocks LA, Farooqui T. Modulation of inflammation in brain: A matter of fat. Journal of Neurochemistry. May 2007;**101**(3):577-599

[105] Meyer RP, Gehlhaus M, Knoth R, Volk B. Expression and function of cytochrome p450 in brain drug metabolism. Current Drug Metabolism. May 2007;**8**(4):297-306

[106] Volk B, Hettmannsperger U, Papp T, Amelizad Z, Oesch F, Knoth R. Mapping of phenytoin-inducible cytochrome P450 immunoreactivity

**31**

*Polyunsaturated Fatty Acid Metabolism in the Brain and Brain Cells*

[114] Fredman G, Serhan

2011;**437**(2):185-197

The Biochemical Journal. Jul.

A, Chiang N, Fredman G, Serhan CN. Resolvin D1 receptor stereoselectivity and regulation of inflammation and proresolving microRNAs. The American Journal of Pathology. May 2012;**180**(5):2018-2027

[115] Krishnamoorthy S, Recchiuti

[116] Recchiuti A, Krishnamoorthy S, Fredman G, Chiang N, Serhan CN. MicroRNAs in resolution of acute inflammation: Identification of novel resolvin D1-miRNA circuits. The FASEB

Journal. Feb. 2011;**25**(2):544-560

[117] Rey C et al. Resolvin D1 and E1 promote resolution of inflammation in microglial cells in vitro. Brain, Behavior, and Immunity. Jul. 2016;**55**:249-259

[118] Aursnes M et al. Total synthesis of the lipid mediator PD1n-3 DPA: Configurational assignments and anti-inflammatory and pro-resolving actions. Journal of Natural Products.

[119] Doyle R, Sadlier DM, Godson C. Pro-resolving lipid mediators: Agents of anti-ageing? Seminars in Immunology. 2018;**40**:36-48

[120] Hong S, Gronert K, Devchand PR, Moussignac RL, Serhan CN. Novel docosatrienes and 17S-resolvins

2003;**278**(17):14677-14687

2017;**136**:12-20

generated from docosahexaenoic acid in murine brain, human blood, and glial cells. Autacoids in anti-inflammation. The Journal of Biological Chemistry.

[121] Kuda O. Bioactive metabolites of docosahexaenoic acid. Biochimie. May

[122] Marcheselli VL et al. Novel docosanoids inhibit brain

Apr. 2014;**77**(4):910-916

CN. Specialized proresolving mediator targets for RvE1 and RvD1 in peripheral blood and mechanisms of resolution.

*DOI: http://dx.doi.org/10.5772/intechopen.88232*

in the mouse central nervous system. Neuroscience. 1991;**42**(1):215-235

[107] Barden AE, Mas E, Mori TA. n-3 Fatty acid supplementation and proresolving mediators of inflammation. Current Opinion in Lipidology. Feb. 2016;**27**(1):26-32

[108] Halade GV, Black LM, Verma MK. Paradigm shift—Metabolic

[109] Recchiuti A. Resolvin D1 and its GPCRs in resolution circuits of inflammation. Prostaglandins & Other Lipid Mediators. Dec. 2013;**107**:64-76

[110] Sun YP et al. Resolvin D1 and its aspirin-triggered 17R epimer. Stereochemical assignments, antiinflammatory properties, and enzymatic inactivation. The Journal of Biological Chemistry. Mar. 2007;**282**(13):9323-9334

[111] Mulik RS, Bing C, Ladouceur-Wodzak M, Munaweera I, Chopra R, Corbin IR. Localized delivery of lowdensity lipoprotein docosahexaenoic acid nanoparticles to the rat brain using focused ultrasound. Biomaterials. Mar.

[112] Sun W et al. Endogenous expression pattern of resolvin D1 in a rat model of self-resolution of lipopolysaccharide-induced acute respiratory distress syndrome and inflammation. International Immunopharmacology. Nov.

[113] Bisicchia E et al. Resolvin D1 halts remote neuroinflammation and improves functional recovery after focal brain damage via ALX/ FPR2 receptor-regulated microRNAs.

Molecular Neurobiology. Aug.

2018;**55**(8):6894-6905

2016;**83**:257-268

2014;**23**(1):247-253

Aug. 2018;**36**(4):935-953

transformation of docosahexaenoic and eicosapentaenoic acids to bioactives exemplify the promise of fatty acid drug discovery. Biotechnology Advances.

*Polyunsaturated Fatty Acid Metabolism in the Brain and Brain Cells DOI: http://dx.doi.org/10.5772/intechopen.88232*

in the mouse central nervous system. Neuroscience. 1991;**42**(1):215-235

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

metabolites of arachidonic acid activate PPARgamma: A possible neuroprotective effect in ischemic brain. Journal of Lipid Research. Mar.

[99] Bystrom J et al. Endogenous epoxygenases are modulators of monocyte/macrophage activity. PLoS

[100] Fleming I. Cytochrome P450 dependent eicosanoid production and crosstalk. Current Opinion in Lipidology. Oct. 2011;**22**(5):403-409

[101] Gilroy DW et al. CYP450-derived oxylipins mediate inflammatory resolution. Proceedings of the National Academy of Sciences of the United States of America. Jun.

2015;**56**(3):502-514

One. 2011;**6**(10):e26591

2016;**113**(23):E3240-E3249

2013;**368**(1612):20120431

1998;**80**(11):899-904

2007;**101**(3):577-599

May 2007;**8**(4):297-306

[104] Farooqui AA, Horrocks LA, Farooqui T. Modulation of inflammation in brain: A matter of fat. Journal of Neurochemistry. May

[105] Meyer RP, Gehlhaus M, Knoth R, Volk B. Expression and function of cytochrome p450 in brain drug metabolism. Current Drug Metabolism.

[106] Volk B, Hettmannsperger U, Papp T, Amelizad Z, Oesch F, Knoth R. Mapping of phenytoin-inducible cytochrome P450 immunoreactivity

[103] Levi G, Minghetti L, Aloisi F. Regulation of prostanoid synthesis in microglial cells and effects of prostaglandin E2 on microglial functions. Biochimie. Nov.

[102] Nebert DW, Wikvall K, Miller WL. Human cytochromes P450 in health and disease. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences.

[90] Shalini S-M et al. Distribution of Alox15 in the rat brain and its role in prefrontal cortical resolvin D1 formation and spatial working memory. Molecular Neurobiology.

[91] Nadjar A et al. NFkappaB activates in vivo the synthesis of inducible Cox-2 in the brain. Journal of Cerebral Blood Flow and Metabolism. Aug.

[92] Navarro-Mabarak C, Camacho-Carranza R, Espinosa-Aguirre JJ. Cytochrome P450 in the central nervous system as a therapeutic target in neurodegenerative diseases. Drug Metabolism Reviews. 2018;**50**(2):95-108

[93] Czapski GA, Gajkowska B, Strosznajder JB. Systemic

administration of lipopolysaccharide induces molecular and morphological alterations in the hippocampus. Brain Research. Oct. 2010;**1356**:85-94

[94] Schwab JM, Chiang N, Arita M, Serhan CN. Resolvin E1 and protectin D1 activate inflammationresolution programmes. Nature. Jun.

[95] Pratico D et al. 12/15-lipoxygenase is increased in Alzheimer's disease: Possible involvement in brain oxidative

stress. The American Journal of Pathology. May 2004;**164**(5):1655-1662

[96] Wang X et al. Resolution of inflammation is altered in Alzheimer's disease. Alzheimer's & Dementia. Jan.

[97] Yigitkanli K, Zheng Y, Pekcec A, Lo EH, van Leyen K. Increased 12/15-lipoxygenase leads to widespread brain injury following global cerebral ischemia. Translational Stroke Research.

[98] Sun L, Xu YW, Han J, Liang H, Wang N, Cheng Y. 12/15-Lipoxygenase

2015;**11**(1):40-50 e1-2

Apr. 2017;**8**(2):194-202

2007;**447**(7146):869-874

2018;**55**(2):1537-1550

2005;**25**(8):1047-1059

**30**

[107] Barden AE, Mas E, Mori TA. n-3 Fatty acid supplementation and proresolving mediators of inflammation. Current Opinion in Lipidology. Feb. 2016;**27**(1):26-32

[108] Halade GV, Black LM, Verma MK. Paradigm shift—Metabolic transformation of docosahexaenoic and eicosapentaenoic acids to bioactives exemplify the promise of fatty acid drug discovery. Biotechnology Advances. Aug. 2018;**36**(4):935-953

[109] Recchiuti A. Resolvin D1 and its GPCRs in resolution circuits of inflammation. Prostaglandins & Other Lipid Mediators. Dec. 2013;**107**:64-76

[110] Sun YP et al. Resolvin D1 and its aspirin-triggered 17R epimer. Stereochemical assignments, antiinflammatory properties, and enzymatic inactivation. The Journal of Biological Chemistry. Mar. 2007;**282**(13):9323-9334

[111] Mulik RS, Bing C, Ladouceur-Wodzak M, Munaweera I, Chopra R, Corbin IR. Localized delivery of lowdensity lipoprotein docosahexaenoic acid nanoparticles to the rat brain using focused ultrasound. Biomaterials. Mar. 2016;**83**:257-268

[112] Sun W et al. Endogenous expression pattern of resolvin D1 in a rat model of self-resolution of lipopolysaccharide-induced acute respiratory distress syndrome and inflammation. International Immunopharmacology. Nov. 2014;**23**(1):247-253

[113] Bisicchia E et al. Resolvin D1 halts remote neuroinflammation and improves functional recovery after focal brain damage via ALX/ FPR2 receptor-regulated microRNAs. Molecular Neurobiology. Aug. 2018;**55**(8):6894-6905

[114] Fredman G, Serhan CN. Specialized proresolving mediator targets for RvE1 and RvD1 in peripheral blood and mechanisms of resolution. The Biochemical Journal. Jul. 2011;**437**(2):185-197

[115] Krishnamoorthy S, Recchiuti A, Chiang N, Fredman G, Serhan CN. Resolvin D1 receptor stereoselectivity and regulation of inflammation and proresolving microRNAs. The American Journal of Pathology. May 2012;**180**(5):2018-2027

[116] Recchiuti A, Krishnamoorthy S, Fredman G, Chiang N, Serhan CN. MicroRNAs in resolution of acute inflammation: Identification of novel resolvin D1-miRNA circuits. The FASEB Journal. Feb. 2011;**25**(2):544-560

[117] Rey C et al. Resolvin D1 and E1 promote resolution of inflammation in microglial cells in vitro. Brain, Behavior, and Immunity. Jul. 2016;**55**:249-259

[118] Aursnes M et al. Total synthesis of the lipid mediator PD1n-3 DPA: Configurational assignments and anti-inflammatory and pro-resolving actions. Journal of Natural Products. Apr. 2014;**77**(4):910-916

[119] Doyle R, Sadlier DM, Godson C. Pro-resolving lipid mediators: Agents of anti-ageing? Seminars in Immunology. 2018;**40**:36-48

[120] Hong S, Gronert K, Devchand PR, Moussignac RL, Serhan CN. Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells. Autacoids in anti-inflammation. The Journal of Biological Chemistry. 2003;**278**(17):14677-14687

[121] Kuda O. Bioactive metabolites of docosahexaenoic acid. Biochimie. May 2017;**136**:12-20

[122] Marcheselli VL et al. Novel docosanoids inhibit brain

ischemia-reperfusion-mediated leukocyte infiltration and proinflammatory gene expression. The Journal of Biological Chemistry. Oct. 2003;**278**(44):43807-43817

[123] Lukiw WJ et al. A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. The Journal of Clinical Investigation. Oct. 2005;**115**(10):2774-2783

[124] Bazan NG et al. Novel aspirintriggered neuroprotectin D1 attenuates cerebral ischemic injury after experimental stroke. Experimental Neurology. Jul. 2012;**236**(1):122-130

[125] Yao C, Zhang J, Chen F, Lin Y. Neuroprotectin D1 attenuates brain damage induced by transient middle cerebral artery occlusion in rats through TRPC6/CREB pathways. Molecular Medicine Reports. Aug. 2013;**8**(2):543-550

[126] Serhan CN et al. Maresins: Novel macrophage mediators with potent antiinflammatory and proresolving actions. The Journal of Experimental Medicine. Jan. 2009;**206**(1):15-23

[127] Zhu M et al. Pro-resolving lipid mediators improve neuronal survival and increase Abeta42 phagocytosis. Molecular Neurobiology. May 2016;**53**(4):2733-2749

[128] Xian W et al. The proresolving lipid mediator Maresin 1 protects against cerebral ischemia/ reperfusion injury by attenuating the pro-inflammatory response. Biochemical and Biophysical Research Communications. Mar. 2016;**472**(1):175-181

[129] Xian W, Li T, Li L, Hu L, Cao J. Maresin 1 attenuates the inflammatory response and mitochondrial damage in mice with cerebral ischemia/reperfusion in a SIRT1-dependent manner. Brain Research. 2019

[130] Francos-Quijorna I et al. Maresin 1 promotes inflammatory resolution, neuroprotection, and functional neurological recovery after spinal cord injury. The Journal of Neuroscience. Nov. 2017;**37**(48):11731-11743

[131] Ohira T, Arita M, Omori K, Recchiuti A, Van Dyke TE, Serhan CN. Resolvin E1 receptor activation signals phosphorylation and phagocytosis. The Journal of Biological Chemistry. Jan. 2010;**285**(5):3451-3461

[132] Isobe Y et al. Identification and structure determination of novel antiinflammatory mediator resolvin E3, 17,18-dihydroxyeicosapentaenoic acid. The Journal of Biological Chemistry. Mar. 2012;**287**(13):10525-10534

[133] Chen CT, Liu Z, Bazinet RP. Rapid de-esterification and loss of eicosapentaenoic acid from rat brain phospholipids: An intracerebroventricular study. Journal of Neurochemistry. Feb. 2011;**116**(3):363-373

[134] Siegert E, Paul F, Rothe M, Weylandt KH. The effect of omega-3 fatty acids on central nervous system remyelination in fat-1 mice. BMC Neuroscience. 2017;**18**(1):19

[135] Krishnamoorthy S et al. Resolvin D1 binds human phagocytes with evidence for proresolving receptors. Proceedings of the National Academy of Sciences of the United States of America. Jan. 2010;**107**(4):1660-1665

[136] Arita M, Ohira T, Sun YP, Elangovan S, Chiang N, Serhan CN. Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation. Journal of Immunology. Mar. 2007;**178**(6):3912-3917

**33**

*Polyunsaturated Fatty Acid Metabolism in the Brain and Brain Cells*

[145] Mizwicki MT et al. 1alpha,25 dihydroxyvitamin D3 and resolvin D1 retune the balance between amyloidbeta phagocytosis and inflammation in Alzheimer's disease patients. Journal of Alzheimer's Disease.

[146] Uno H et al. Immunonutrition suppresses acute inflammatory responses through modulation of resolvin E1 in patients undergoing major hepatobiliary resection. Surgery.

[147] Hiram R et al. Resolvin E1

[148] Gyurko R, Van Dyke TE. The role of polyunsaturated ω-3 fatty acid eicosapentaenoic acid-derived resolvin E1 (RvE1) in bone preservation. Critical Reviews in Immunology.

[149] Abdelmoaty S et al. Spinal actions of lipoxin A4 and 17(R)-resolvin D1 attenuate inflammation-induced mechanical hypersensitivity and spinal TNF release. PLoS One.

[150] Rossi S et al. Protection from endotoxic uveitis by intravitreal resolvin D1: Involvement of lymphocytes, miRNAs, ubiquitin-proteasome, and M1/M2 macrophages. Mediators of Inflammation. 2015;**2015**:149381

[151] Titos E et al. Resolvin D1 and its precursor docosahexaenoic acid promote resolution of adipose tissue inflammation by eliciting macrophage polarization toward an M2-like phenotype. Journal of Immunology. Nov. 2011;**187**(10):5408-5418

normalizes contractility, Ca2+ sensitivity and smooth muscle cell migration rate in TNF-α- and IL-6-pretreated human pulmonary arteries. American Journal of Physiology. Lung Cellular and Molecular Physiology. Oct.

2013;**34**(1):155-170

2016;**160**(1):228-236

2015;**309**(8):L776-L788

2014;**34**(4):347-357

2013;**8**(9):e75543

*DOI: http://dx.doi.org/10.5772/intechopen.88232*

[137] Ho CF-Y et al. Localisation of formyl-peptide receptor 2 in the rat central nervous system and its role in axonal and dendritic outgrowth. Neurochemical Research. Aug.

[138] Guo X et al. Chronic mild restraint stress rats decreased

CMKLR1 expression in distinct brain region. Neuroscience Letters. Aug.

[139] Graham KL et al. Chemokine-like receptor-1 expression by central nervous system-infiltrating leukocytes and involvement in a model of autoimmune demyelinating disease. Journal of Immunology. 2009;**183**(10):6717-6723

[140] Xu ZZ et al. Resolvins RvE1 and RvD1 attenuate inflammatory pain via central and peripheral actions. Nature Medicine. May 2010;**16**(5):592-597, 1p

[141] Qu L, Caterina MJ. Accelerating the reversal of inflammatory pain with NPD1 and its receptor GPR37. The Journal of Clinical Investigation. Aug.

[142] Colas RA, Shinohara M, Dalli J, Chiang N, Serhan CN. Identification and signature profiles for pro-resolving and inflammatory lipid mediators in human tissue. American Journal of Physiology-Cell Physiology. Jul.

[143] Serhan CN, Chiang N, Dalli J. New pro-resolving n-3 mediators bridge resolution of infectious inflammation to tissue regeneration. Molecular Aspects

of Medicine. Dec. 2018;**64**:1-17

[144] Famenini S et al. Increased intermediate M1-M2 macrophage polarization and improved cognition in mild cognitive impairment patients on omega-3 supplementation. The FASEB Journal. Jan. 2017;**31**(1):148-160

2018;**43**(8):1587-1598

2012;**524**(1):25-29

following 597

2018;**128**(8):3246-3249

2014;**307**(1):C39-C54

*Polyunsaturated Fatty Acid Metabolism in the Brain and Brain Cells DOI: http://dx.doi.org/10.5772/intechopen.88232*

[137] Ho CF-Y et al. Localisation of formyl-peptide receptor 2 in the rat central nervous system and its role in axonal and dendritic outgrowth. Neurochemical Research. Aug. 2018;**43**(8):1587-1598

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

in a SIRT1-dependent manner. Brain

[130] Francos-Quijorna I et al. Maresin 1 promotes inflammatory resolution, neuroprotection, and functional neurological recovery after spinal cord injury. The Journal of Neuroscience. Nov. 2017;**37**(48):11731-11743

[131] Ohira T, Arita M, Omori K, Recchiuti A, Van Dyke TE, Serhan CN. Resolvin E1 receptor activation signals phosphorylation and

phagocytosis. The Journal of Biological Chemistry. Jan. 2010;**285**(5):3451-3461

[132] Isobe Y et al. Identification and structure determination of novel antiinflammatory mediator resolvin E3, 17,18-dihydroxyeicosapentaenoic acid. The Journal of Biological Chemistry. Mar. 2012;**287**(13):10525-10534

[133] Chen CT, Liu Z, Bazinet RP. Rapid de-esterification and loss of eicosapentaenoic acid from rat brain phospholipids: An intracerebroventricular study. Journal of Neurochemistry. Feb.

[134] Siegert E, Paul F, Rothe M, Weylandt KH. The effect of omega-3 fatty acids on central nervous system remyelination in fat-1 mice. BMC Neuroscience. 2017;**18**(1):19

[135] Krishnamoorthy S et al. Resolvin D1 binds human phagocytes with evidence for proresolving receptors. Proceedings of the National Academy of Sciences of the United States of America. Jan. 2010;**107**(4):1660-1665

[136] Arita M, Ohira T, Sun YP, Elangovan S, Chiang N, Serhan CN. Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation. Journal of Immunology. Mar. 2007;**178**(6):3912-3917

2011;**116**(3):363-373

Research. 2019

ischemia-reperfusion-mediated leukocyte infiltration and proinflammatory gene expression. The Journal of Biological Chemistry. Oct.

2003;**278**(44):43807-43817

2005;**115**(10):2774-2783

[123] Lukiw WJ et al. A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. The Journal of Clinical Investigation. Oct.

[124] Bazan NG et al. Novel aspirintriggered neuroprotectin D1 attenuates

cerebral ischemic injury after experimental stroke. Experimental Neurology. Jul. 2012;**236**(1):122-130

[125] Yao C, Zhang J, Chen F, Lin Y. Neuroprotectin D1 attenuates brain damage induced by transient middle cerebral artery occlusion in rats through TRPC6/CREB pathways. Molecular Medicine Reports. Aug.

[126] Serhan CN et al. Maresins: Novel macrophage mediators with potent antiinflammatory and proresolving actions. The Journal of Experimental Medicine. Jan. 2009;**206**(1):15-23

[127] Zhu M et al. Pro-resolving lipid mediators improve neuronal survival and increase Abeta42 phagocytosis. Molecular Neurobiology. May

2013;**8**(2):543-550

2016;**53**(4):2733-2749

2016;**472**(1):175-181

[128] Xian W et al. The pro-

resolving lipid mediator Maresin 1 protects against cerebral ischemia/ reperfusion injury by attenuating the pro-inflammatory response. Biochemical and Biophysical Research Communications. Mar.

[129] Xian W, Li T, Li L, Hu L, Cao J. Maresin 1 attenuates the inflammatory response and mitochondrial damage in mice with cerebral ischemia/reperfusion

**32**

[138] Guo X et al. Chronic mild restraint stress rats decreased CMKLR1 expression in distinct brain region. Neuroscience Letters. Aug. 2012;**524**(1):25-29

[139] Graham KL et al. Chemokine-like receptor-1 expression by central nervous system-infiltrating leukocytes and involvement in a model of autoimmune demyelinating disease. Journal of Immunology. 2009;**183**(10):6717-6723

[140] Xu ZZ et al. Resolvins RvE1 and RvD1 attenuate inflammatory pain via central and peripheral actions. Nature Medicine. May 2010;**16**(5):592-597, 1p following 597

[141] Qu L, Caterina MJ. Accelerating the reversal of inflammatory pain with NPD1 and its receptor GPR37. The Journal of Clinical Investigation. Aug. 2018;**128**(8):3246-3249

[142] Colas RA, Shinohara M, Dalli J, Chiang N, Serhan CN. Identification and signature profiles for pro-resolving and inflammatory lipid mediators in human tissue. American Journal of Physiology-Cell Physiology. Jul. 2014;**307**(1):C39-C54

[143] Serhan CN, Chiang N, Dalli J. New pro-resolving n-3 mediators bridge resolution of infectious inflammation to tissue regeneration. Molecular Aspects of Medicine. Dec. 2018;**64**:1-17

[144] Famenini S et al. Increased intermediate M1-M2 macrophage polarization and improved cognition in mild cognitive impairment patients on omega-3 supplementation. The FASEB Journal. Jan. 2017;**31**(1):148-160

[145] Mizwicki MT et al. 1alpha,25 dihydroxyvitamin D3 and resolvin D1 retune the balance between amyloidbeta phagocytosis and inflammation in Alzheimer's disease patients. Journal of Alzheimer's Disease. 2013;**34**(1):155-170

[146] Uno H et al. Immunonutrition suppresses acute inflammatory responses through modulation of resolvin E1 in patients undergoing major hepatobiliary resection. Surgery. 2016;**160**(1):228-236

[147] Hiram R et al. Resolvin E1 normalizes contractility, Ca2+ sensitivity and smooth muscle cell migration rate in TNF-α- and IL-6-pretreated human pulmonary arteries. American Journal of Physiology. Lung Cellular and Molecular Physiology. Oct. 2015;**309**(8):L776-L788

[148] Gyurko R, Van Dyke TE. The role of polyunsaturated ω-3 fatty acid eicosapentaenoic acid-derived resolvin E1 (RvE1) in bone preservation. Critical Reviews in Immunology. 2014;**34**(4):347-357

[149] Abdelmoaty S et al. Spinal actions of lipoxin A4 and 17(R)-resolvin D1 attenuate inflammation-induced mechanical hypersensitivity and spinal TNF release. PLoS One. 2013;**8**(9):e75543

[150] Rossi S et al. Protection from endotoxic uveitis by intravitreal resolvin D1: Involvement of lymphocytes, miRNAs, ubiquitin-proteasome, and M1/M2 macrophages. Mediators of Inflammation. 2015;**2015**:149381

[151] Titos E et al. Resolvin D1 and its precursor docosahexaenoic acid promote resolution of adipose tissue inflammation by eliciting macrophage polarization toward an M2-like phenotype. Journal of Immunology. Nov. 2011;**187**(10):5408-5418

[152] Li L et al. Resolvin D1 promotes the interleukin-4-induced alternative activation in BV-2 microglial cells. Journal of Neuroinflammation. 2014;**11**:72

[153] Kantarci A et al. Combined administration of resolvin E1 and lipoxin A4 resolves inflammation in a murine model of Alzheimer's disease. Experimental Neurology. 2018;**300**:111-120

[154] Harrison JL et al. Resolvins AT-D1 and E1 differentially impact functional outcome, post-traumatic sleep, and microglial activation following diffuse brain injury in the mouse. Brain, Behavior, and Immunity. Jul. 2015;**47**:131-140

[155] Xu MX et al. Resolvin D1, an endogenous lipid mediator for inactivation of inflammation-related signaling pathways in microglial cells, prevents lipopolysaccharideinduced inflammatory responses. CNS Neuroscience & Therapeutics. Apr. 2013;**19**(4):235-243

[156] Terrando N et al. Aspirin-triggered resolvin D1 prevents surgery-induced cognitive decline. The FASEB Journal. Sep. 2013;**27**(9):3564-3571

[157] Luo C et al. Enriched endogenous omega-3 fatty acids in mice protect against global ischemia injury. Journal of Lipid Research. Jul. 2014;**55**(7):1288-1297

[158] Furuyashiki T, Akiyama S, Kitaoka S. Roles of multiple lipid mediators in stress and depression. International Immunology. 2019

[159] Deyama S et al. Resolvin D1 and D2 reverse lipopolysaccharideinduced depression-like behaviors through the mTORC1 signaling pathway. The International Journal of Neuropsychopharmacology. Jul. 2017;**20**(7):575-584

[160] Deyama S et al. Resolvin E1/ E2 ameliorate lipopolysaccharideinduced depression-like behaviors via ChemR23. Psychopharmacology. 2018;**235**(1):329-336

[161] Deyama S, Shimoda K, Ikeda H, Fukuda H, Shuto S, Minami M. Resolvin E3 attenuates lipopolysaccharideinduced depression-like behavior in mice. Journal of Pharmacological Sciences. Sep. 2018;**138**(1):86-88

[162] Klein CP, Sperotto ND, Maciel IS, Leite CE, Souza AH, Campos MM. Effects of D-series resolvins on behavioral and neurochemical changes in a fibromyalgia-like model in mice. Neuropharmacology. Nov. 2014;**86**:57-66

[163] Gilbert K, Bernier J, Godbout R, Rousseau G. Resolvin D1, a metabolite of omega-3 polyunsaturated fatty acid, decreases post-myocardial infarct depression. Marine Drugs. Nov. 2014;**12**(11):5396-5407

[164] Ishikawa Y et al. Rapid and sustained antidepressant effects of resolvin D1 and D2 in a chronic unpredictable stress model. Behavioural Brain Research. Aug. 2017;**332**:233-236

[165] Zhu M, Wang X, Schultzberg M, Hjorth E. Differential regulation of resolution in inflammation induced by amyloid-β42 and lipopolysaccharides in human microglia. Journal of Alzheimer's Disease. 2015;**43**(4):1237-1250

[166] Tian Y, Zhang Y, Zhang R, Qiao S, Fan J. Resolvin D2 recovers neural injury by suppressing inflammatory mediators expression in lipopolysaccharideinduced Parkinson's disease rat model. Biochemical and Biophysical Research Communications. May 2015;**460**(3):799-805

[167] Shevalye H et al. Effect of enriching the diet with menhaden oil or daily treatment with resolvin D1 on

**35**

*Polyunsaturated Fatty Acid Metabolism in the Brain and Brain Cells*

[175] Rosenberger TA et al. Rat brain arachidonic acid

2004;**88**(5):1168-1178

2017;**54**(6):4303-4315

2002;**507**:457-462

and Life Sciences. Aug. 2013;**932**:123-133

[179] Slepko N, Minghetti L, Polazzi E, Nicolini A, Levi G. Reorientation of prostanoid

of Neuroscience Research. Aug. 1997;**49**(3):292-300

[181] Jung YS et al. Probucol inhibits LPS-induced microglia activation and ameliorates brain ischemic injury in normal and hyperlipidemic mice. Acta Pharmacologica Sinica. Aug. 2016;**37**(8):1031-1044

production accompanies 'activation' of adult microglial cells in culture. Journal

[180] Wang C, Wang M, Zhou Y, Dupree JL, Han X. Alterations in mouse brain lipidome after disruption of CST gene: A lipidomics study. Molecular Neurobiology. Aug. 2014;**50**(1):88-96

[176] Taha AY et al. Dietary linoleic acid lowering reduces lipopolysaccharide-induced increase in brain arachidonic acid metabolism.

Molecular Neurobiology. Aug.

[177] Dieter P, Scheibe R, Kamionka S, Kolada A. LPS-induced synthesis and release of PGE2 in liver macrophages: Regulation by CPLA2, COX-1, COX-2, and PGE2 synthase. Advances in Experimental Medicine and Biology.

[178] Le Faouder P et al. LC-MS/MS method for rapid and concomitant quantification of pro-inflammatory and pro-resolving polyunsaturated fatty acid metabolites. Journal of Chromatography. B, Analytical Technologies in the Biomedical

metabolism is increased by a 6-day intracerebral ventricular infusion of bacterial lipopolysaccharide. Journal of Neurochemistry. Mar.

*DOI: http://dx.doi.org/10.5772/intechopen.88232*

neuropathy in a mouse model of type 2 diabetes. Journal of Neurophysiology.

[168] Hashimoto M et al. n-3 fatty acids effectively improve the reference memory-related learning ability associated with increased brain docosahexaenoic acidderived docosanoids in aged rats. Biochimica et Biophysica Acta. Feb.

[169] Taha AY et al. Regulation of rat plasma and cerebral cortex oxylipin concentrations with increasing levels of dietary linoleic acid. Prostaglandins, Leukotrienes & Essential Fatty Acids. 2016

[170] Ostermann AI et al. A diet rich in omega-3 fatty acids enhances expression of soluble epoxide hydrolase in murine brain. Prostaglandins & Other Lipid Mediators. Nov. 2017;**133**:79-87

[171] Farias SE, Basselin M, Chang L, Heidenreich KA, Rapoport SI, Murphy RC. Formation of eicosanoids, E2/D2 isoprostanes, and docosanoids following

decapitation-induced ischemia, measured in high-energy-microwaved rat brain. Journal of Lipid Research.

[172] Yang G, Pan F, Gan WB. Stably maintained dendritic spines are associated with lifelong memories. Nature. Dec. 2009;**462**(7275):920-924

[173] Balvers MG et al. Fish oil and inflammatory status alter the n-3 to n-6 balance of the endocannabinoid and oxylipin metabolomes in mouse plasma and tissues. Metabolomics. Dec.

[174] Willenberg I, Rund K, Rong S, Shushakova N, Gueler F, Schebb NH. Characterization of changes in plasma and tissue oxylipin levels in LPS and CLP induced murine sepsis. Inflammation Research. Feb.

2012;**8**(6):1130-1147

2016;**65**(2):133-142

Sep. 2008;**49**(9):1990-2000

Jul. 2015;**114**(1):199-208

2015;**1851**(2):203-209

*Polyunsaturated Fatty Acid Metabolism in the Brain and Brain Cells DOI: http://dx.doi.org/10.5772/intechopen.88232*

neuropathy in a mouse model of type 2 diabetes. Journal of Neurophysiology. Jul. 2015;**114**(1):199-208

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

[160] Deyama S et al. Resolvin E1/ E2 ameliorate lipopolysaccharideinduced depression-like behaviors via ChemR23. Psychopharmacology.

[161] Deyama S, Shimoda K, Ikeda H, Fukuda H, Shuto S, Minami M. Resolvin E3 attenuates lipopolysaccharideinduced depression-like behavior in mice. Journal of Pharmacological Sciences. Sep. 2018;**138**(1):86-88

[162] Klein CP, Sperotto ND, Maciel IS, Leite CE, Souza AH, Campos MM. Effects of D-series resolvins on behavioral and neurochemical changes in a fibromyalgia-like model in mice. Neuropharmacology. Nov.

[163] Gilbert K, Bernier J, Godbout R, Rousseau G. Resolvin D1, a metabolite of omega-3 polyunsaturated fatty acid, decreases post-myocardial infarct depression. Marine Drugs. Nov.

2018;**235**(1):329-336

2014;**86**:57-66

2014;**12**(11):5396-5407

[164] Ishikawa Y et al. Rapid and sustained antidepressant effects of resolvin D1 and D2 in a chronic unpredictable stress model. Behavioural Brain Research. Aug. 2017;**332**:233-236

[165] Zhu M, Wang X, Schultzberg M, Hjorth E. Differential regulation of resolution in inflammation induced by amyloid-β42 and lipopolysaccharides in human microglia. Journal of Alzheimer's

[166] Tian Y, Zhang Y, Zhang R, Qiao S, Fan J. Resolvin D2 recovers neural injury by suppressing inflammatory mediators expression in lipopolysaccharideinduced Parkinson's disease rat model. Biochemical and Biophysical Research Communications. May

Disease. 2015;**43**(4):1237-1250

2015;**460**(3):799-805

[167] Shevalye H et al. Effect of enriching the diet with menhaden oil or daily treatment with resolvin D1 on

[152] Li L et al. Resolvin D1 promotes the interleukin-4-induced alternative activation in BV-2 microglial cells. Journal of Neuroinflammation.

[153] Kantarci A et al. Combined administration of resolvin E1 and lipoxin A4 resolves inflammation in a murine model of Alzheimer's disease. Experimental Neurology.

[154] Harrison JL et al. Resolvins AT-D1 and E1 differentially impact functional

outcome, post-traumatic sleep, and microglial activation following diffuse brain injury in the mouse. Brain, Behavior, and Immunity. Jul.

[155] Xu MX et al. Resolvin D1, an endogenous lipid mediator for inactivation of inflammation-related signaling pathways in microglial cells, prevents lipopolysaccharideinduced inflammatory responses. CNS Neuroscience & Therapeutics. Apr.

[156] Terrando N et al. Aspirin-triggered resolvin D1 prevents surgery-induced cognitive decline. The FASEB Journal.

[157] Luo C et al. Enriched endogenous omega-3 fatty acids in mice protect against global ischemia injury. Journal of Lipid Research. Jul.

[158] Furuyashiki T, Akiyama S, Kitaoka S. Roles of multiple lipid mediators in stress and depression. International

[159] Deyama S et al. Resolvin D1 and D2 reverse lipopolysaccharideinduced depression-like behaviors through the mTORC1 signaling pathway. The International Journal of Neuropsychopharmacology. Jul.

2014;**11**:72

2018;**300**:111-120

2015;**47**:131-140

2013;**19**(4):235-243

Sep. 2013;**27**(9):3564-3571

2014;**55**(7):1288-1297

Immunology. 2019

2017;**20**(7):575-584

**34**

[168] Hashimoto M et al. n-3 fatty acids effectively improve the reference memory-related learning ability associated with increased brain docosahexaenoic acidderived docosanoids in aged rats. Biochimica et Biophysica Acta. Feb. 2015;**1851**(2):203-209

[169] Taha AY et al. Regulation of rat plasma and cerebral cortex oxylipin concentrations with increasing levels of dietary linoleic acid. Prostaglandins, Leukotrienes & Essential Fatty Acids. 2016

[170] Ostermann AI et al. A diet rich in omega-3 fatty acids enhances expression of soluble epoxide hydrolase in murine brain. Prostaglandins & Other Lipid Mediators. Nov. 2017;**133**:79-87

[171] Farias SE, Basselin M, Chang L, Heidenreich KA, Rapoport SI, Murphy RC. Formation of eicosanoids, E2/D2 isoprostanes, and docosanoids following decapitation-induced ischemia, measured in high-energy-microwaved rat brain. Journal of Lipid Research. Sep. 2008;**49**(9):1990-2000

[172] Yang G, Pan F, Gan WB. Stably maintained dendritic spines are associated with lifelong memories. Nature. Dec. 2009;**462**(7275):920-924

[173] Balvers MG et al. Fish oil and inflammatory status alter the n-3 to n-6 balance of the endocannabinoid and oxylipin metabolomes in mouse plasma and tissues. Metabolomics. Dec. 2012;**8**(6):1130-1147

[174] Willenberg I, Rund K, Rong S, Shushakova N, Gueler F, Schebb NH. Characterization of changes in plasma and tissue oxylipin levels in LPS and CLP induced murine sepsis. Inflammation Research. Feb. 2016;**65**(2):133-142

[175] Rosenberger TA et al. Rat brain arachidonic acid metabolism is increased by a 6-day intracerebral ventricular infusion of bacterial lipopolysaccharide. Journal of Neurochemistry. Mar. 2004;**88**(5):1168-1178

[176] Taha AY et al. Dietary linoleic acid lowering reduces lipopolysaccharide-induced increase in brain arachidonic acid metabolism. Molecular Neurobiology. Aug. 2017;**54**(6):4303-4315

[177] Dieter P, Scheibe R, Kamionka S, Kolada A. LPS-induced synthesis and release of PGE2 in liver macrophages: Regulation by CPLA2, COX-1, COX-2, and PGE2 synthase. Advances in Experimental Medicine and Biology. 2002;**507**:457-462

[178] Le Faouder P et al. LC-MS/MS method for rapid and concomitant quantification of pro-inflammatory and pro-resolving polyunsaturated fatty acid metabolites. Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. Aug. 2013;**932**:123-133

[179] Slepko N, Minghetti L, Polazzi E, Nicolini A, Levi G. Reorientation of prostanoid production accompanies 'activation' of adult microglial cells in culture. Journal of Neuroscience Research. Aug. 1997;**49**(3):292-300

[180] Wang C, Wang M, Zhou Y, Dupree JL, Han X. Alterations in mouse brain lipidome after disruption of CST gene: A lipidomics study. Molecular Neurobiology. Aug. 2014;**50**(1):88-96

[181] Jung YS et al. Probucol inhibits LPS-induced microglia activation and ameliorates brain ischemic injury in normal and hyperlipidemic mice. Acta Pharmacologica Sinica. Aug. 2016;**37**(8):1031-1044

**37**

Section 3

Carbohydrates

and the Brain

[182] Kim HW, Rao JS, Rapoport SI, Igarashi M. Dietary n-6 PUFA deprivation downregulates arachidonate but upregulates docosahexaenoate metabolizing enzymes in rat brain. Biochimica et Biophysica Acta. Feb. 2011;**1811**(2):111-117

Section 3

Carbohydrates and the Brain

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

[182] Kim HW, Rao JS, Rapoport SI, Igarashi M. Dietary n-6 PUFA deprivation downregulates arachidonate but upregulates docosahexaenoate metabolizing enzymes in rat brain. Biochimica et Biophysica Acta. Feb.

2011;**1811**(2):111-117

**36**

**39**

**Chapter 3**

**Abstract**

impact of sugars on the brain.

**1. Introduction**

Carbohydrates and the Brain:

Even if its size is fairly small (about 2% of body weight), the brain consumes around 20% of the total body energy. Whereas organs such as muscles and liver may use several sources of energy, under physiological conditions, the brain mainly depends on glucose for its energy needs. This involves the need for blood glucose level to be tightly regulated. Thus, in addition to its fueling role, glucose plays a role as signaling molecule informing the brain of any slight change in blood level to ensure glucose homeostasis. In this chapter, we will describe the fueling and sensing properties of glucose and other carbohydrates on the brain and present some physiological brain functions impacted by these sugars. We will also highlight the scientific questions that need to be answered in order to better understand the

**Keywords:** brain, glucose, fructose, food intake, glucose-sensing neurons

homeostasis and appropriate fueling of brain cells.

The mammalian brain essentially depends on glucose for its energy needs. Because neurons have the highest energy demand in the adult brain, they require continuous delivery of glucose from the blood. In man, the brain represents ~2% of the body weight but uses ~20% of glucose-derived energy, making it the main consumer of glucose [1]. As a consequence, a tight regulation of glucose metabolism is critical for brain physiology. A fine feedback loop between the brain and various organs and tissues has been demonstrated, allowing, in normal conditions, to maintain blood glucose level rather constant around 1 g/l (7–8 mM) in the blood and ~2 mM in the brain (see below Section 5) [2, 3]. The brain needs a precise and clear feedback on the metabolic state of the whole body [4]. To achieve this aim, various brain areas, especially the brainstem and the hypothalamus, integrate peripheral signals delivered by neural input from various organs, as well as by metabolites (glucose, fatty acids) and hormones (leptin, insulin, ghrelin) via the blood [2–4]. Thus, specialized nutrients- and hormones-sensing neurons in which the firing rate varies in response to changes in extra-cellular nutrients or hormones concentration have been described. In response, the brain will generate appropriate response by modulating food intake and peripheral organs' activity via the autonomic nervous system to maintain energy status and glucose homeostasis (**Figure 1**). Thus, we will describe in this chapter that in the central nervous system, glucose has a dual role and is considered as a fueling as well as a sensing metabolite to ensure glucose

Roles and Impact

*Xavier Fioramonti and Luc Pénicaud*

## **Chapter 3**

## Carbohydrates and the Brain: Roles and Impact

*Xavier Fioramonti and Luc Pénicaud*

## **Abstract**

Even if its size is fairly small (about 2% of body weight), the brain consumes around 20% of the total body energy. Whereas organs such as muscles and liver may use several sources of energy, under physiological conditions, the brain mainly depends on glucose for its energy needs. This involves the need for blood glucose level to be tightly regulated. Thus, in addition to its fueling role, glucose plays a role as signaling molecule informing the brain of any slight change in blood level to ensure glucose homeostasis. In this chapter, we will describe the fueling and sensing properties of glucose and other carbohydrates on the brain and present some physiological brain functions impacted by these sugars. We will also highlight the scientific questions that need to be answered in order to better understand the impact of sugars on the brain.

**Keywords:** brain, glucose, fructose, food intake, glucose-sensing neurons

## **1. Introduction**

The mammalian brain essentially depends on glucose for its energy needs. Because neurons have the highest energy demand in the adult brain, they require continuous delivery of glucose from the blood. In man, the brain represents ~2% of the body weight but uses ~20% of glucose-derived energy, making it the main consumer of glucose [1]. As a consequence, a tight regulation of glucose metabolism is critical for brain physiology. A fine feedback loop between the brain and various organs and tissues has been demonstrated, allowing, in normal conditions, to maintain blood glucose level rather constant around 1 g/l (7–8 mM) in the blood and ~2 mM in the brain (see below Section 5) [2, 3]. The brain needs a precise and clear feedback on the metabolic state of the whole body [4]. To achieve this aim, various brain areas, especially the brainstem and the hypothalamus, integrate peripheral signals delivered by neural input from various organs, as well as by metabolites (glucose, fatty acids) and hormones (leptin, insulin, ghrelin) via the blood [2–4]. Thus, specialized nutrients- and hormones-sensing neurons in which the firing rate varies in response to changes in extra-cellular nutrients or hormones concentration have been described. In response, the brain will generate appropriate response by modulating food intake and peripheral organs' activity via the autonomic nervous system to maintain energy status and glucose homeostasis (**Figure 1**). Thus, we will describe in this chapter that in the central nervous system, glucose has a dual role and is considered as a fueling as well as a sensing metabolite to ensure glucose homeostasis and appropriate fueling of brain cells.

#### **Figure 1.**

*Role of the brain in the control of energy homeostasis. The brain integrates peripheral signals delivered by neural input from various organs, as well as by metabolites (glucose and fatty acids) and hormones (leptin, insulin, and ghrelin) via the blood. In response, the brain generates appropriate response by modulating food intake and peripheral organs' activity via the autonomic nervous system to maintain energy homeostasis.*

However, one has to keep in mind that given the dietary mutations that occurred in recent decades, sugars other than glucose are part of our diet and could influence brain fueling and sensing. This is indeed the case for example of fructose. Fructose and glucose are rather simple molecules but there are differences in the way the body processes them. This is definitely true for the way the brain uses and reacts to them. These differences could explain the consequences observed after a high consumption of fructose, on food intake and whole-body glucose metabolism.

#### **2. Brain's control of glycemia**

In humans, the value for normoglycemia is around 1 g/l. Although the endocrine pancreas is the main regulator of blood glucose level via the secretion of insulin and glucagon, the brain plays a major role in controlling glycemia. This is achieved through different pathways involving the autonomic nervous system and its projection to several organs and tissues such as the endocrine pancreas, the adrenal gland, the liver, skeletal muscles, and white and brown adipose tissues. As illustrated in **Figure 2**, in case of a drop in blood glucose, there is an activation of sympathetic nerves and consequently an increase in glucagon secretion by the alpha cells and a decrease in that of insulin by the beta cells of the pancreas, as well as an increase in epinephrine and cortisol secretion by the adrenal gland. These changes in hormone levels together with a direct effect of the sympathetic system will lead to an increased glucose production by the liver, and a decreased glucose utilization by fat deposits and muscles, leading thus to a normalization of blood glucose.

**41**

**Figure 2.**

**3. Glucose: the fuel of brain's neurons**

*blood glucose levels and restore euglycemia.*

Brain function and glucose metabolism are intimately linked [1]. Indeed, glucose is the main, if not the only, energy substrate of this organ. Hypoglycemia (below 0.7 g/l) causes rapid brain repercussions, but fortunately, most of the time quickly

*Neuroendocrine pathways involved in the counter-regulatory response to hypoglycemia. Decreased blood glucose is detected by central (hypothalamus and hindbrain) and peripheral (pancreas, hepatoportal vein, and carotid body) glucose sensors. Together, these glucose sensors coordinate physiological responses, which raise blood glucose levels. The initial response to hypoglycemia involves activation of the autonomic nervous system (ANS), inhibition of insulin secretion, and stimulation of pituitary ACTH secretion. Activation of the autonomic nervous system increases glucagon and epinephrine secretion from the pancreas and adrenal medulla, respectively. ACTH stimulates cortisol release from the adrenal cortex. Increased glucagon, epinephrine, and cortisol together with decreased insulin stimulate hepatic glucose production and decrease adipose and muscle glucose uptake. The net result of the neuroendocrine counter-regulatory response to hypoglycemia is to increase* 

*Carbohydrates and the Brain: Roles and Impact DOI: http://dx.doi.org/10.5772/intechopen.88366* *Carbohydrates and the Brain: Roles and Impact DOI: http://dx.doi.org/10.5772/intechopen.88366*

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

However, one has to keep in mind that given the dietary mutations that occurred in recent decades, sugars other than glucose are part of our diet and could influence brain fueling and sensing. This is indeed the case for example of fructose. Fructose and glucose are rather simple molecules but there are differences in the way the body processes them. This is definitely true for the way the brain uses and reacts to them. These differences could explain the consequences observed after a high consumption of fructose, on food intake and whole-body

*Role of the brain in the control of energy homeostasis. The brain integrates peripheral signals delivered by neural input from various organs, as well as by metabolites (glucose and fatty acids) and hormones (leptin, insulin, and ghrelin) via the blood. In response, the brain generates appropriate response by modulating food intake and peripheral organs' activity via the autonomic nervous system to maintain energy homeostasis.*

In humans, the value for normoglycemia is around 1 g/l. Although the endocrine pancreas is the main regulator of blood glucose level via the secretion of insulin and glucagon, the brain plays a major role in controlling glycemia. This is achieved through different pathways involving the autonomic nervous system and its projection to several organs and tissues such as the endocrine pancreas, the adrenal gland, the liver, skeletal muscles, and white and brown adipose tissues. As illustrated in **Figure 2**, in case of a drop in blood glucose, there is an activation of sympathetic nerves and consequently an increase in glucagon secretion by the alpha cells and a decrease in that of insulin by the beta cells of the pancreas, as well as an increase in epinephrine and cortisol secretion by the adrenal gland. These changes in hormone levels together with a direct effect of the sympathetic system will lead to an increased glucose production by the liver, and a decreased glucose utilization by fat deposits and muscles, leading thus to a normalization of

**40**

blood glucose.

glucose metabolism.

**Figure 1.**

**2. Brain's control of glycemia**

#### **Figure 2.**

*Neuroendocrine pathways involved in the counter-regulatory response to hypoglycemia. Decreased blood glucose is detected by central (hypothalamus and hindbrain) and peripheral (pancreas, hepatoportal vein, and carotid body) glucose sensors. Together, these glucose sensors coordinate physiological responses, which raise blood glucose levels. The initial response to hypoglycemia involves activation of the autonomic nervous system (ANS), inhibition of insulin secretion, and stimulation of pituitary ACTH secretion. Activation of the autonomic nervous system increases glucagon and epinephrine secretion from the pancreas and adrenal medulla, respectively. ACTH stimulates cortisol release from the adrenal cortex. Increased glucagon, epinephrine, and cortisol together with decreased insulin stimulate hepatic glucose production and decrease adipose and muscle glucose uptake. The net result of the neuroendocrine counter-regulatory response to hypoglycemia is to increase blood glucose levels and restore euglycemia.*

## **3. Glucose: the fuel of brain's neurons**

Brain function and glucose metabolism are intimately linked [1]. Indeed, glucose is the main, if not the only, energy substrate of this organ. Hypoglycemia (below 0.7 g/l) causes rapid brain repercussions, but fortunately, most of the time quickly

reversible after correction of hypoglycemia. With regard to hyperglycemia, acute situations such as ketoacidosis and hyperosmolarity can lead to a coma, with significant mortality. The chronic effects of hyperglycemia on the brain remain unclear, apart from the risk of ischemic stroke. However, microangiopathy is intimately linked to chronic hyperglycemia, and can cause irreversible diffuse vascular lesions and cerebral ischemia, resulting in cortical atrophy and diabetic encephalopathy.

The brain uses glucose as its main source of energy, although it can utilize other metabolites (mainly ketone bodies) in special situations such as fasting. It has very high energy consumption for its size, mainly due to the high energy supply needed to maintain its functions (potential difference across nerve cell membranes, transport along axons and dendrites, tissue plasticity and repair).

Glucose enters the brain by facilitated diffusion across the blood-brain barrier, and enters brain cells mainly via a range of glucose transporters. Most human cells import glucose by members of the GLUT (SLC2A) family of membrane transport proteins (see review [5]). Of these, GLUT1 is abundant at the BBB and in astrocytes, regulated mainly by steady-state levels of plasma glucose. GLUT2 appears to serve glucose sensors in the brain. GLUT3 ensures efficient glucose uptake by neurons. Although the brain is considered as a non-insulin-dependent organ, insulin crosses the blood-brain barrier and binds to receptors on neurons and glial cells [6]. There is controversy as to whether insulin resistance for glucose is present in the CNS, but emerging data suggest that insulin insensitivity may play an important role in the pathogenesis of obesity, type 2 diabetes, and Alzheimer's disease [7, 8]. GLUT5 and GLUT7 are present at low levels in the brain and have specificity for fructose. GLUT6 is expressed in the brain but has low affinity to glucose. Studies of mice suggest roles of GLUT8 in hippocampal neuronal proliferation. GLUT13 is a myoinositol transporter expressed primarily in the brain and is the only GLUT protein that appears to function as a proton-coupled symporter (see review [5]).

Once transported into the cell, glucose is phosphorylated by a hexokinase, an enzyme with such high affinity toward glucose that it rapidly transforms glucose into glucose-6-phosphate. Glucose-6-phosphate is metabolized further, mainly in the glycolytic pathway, where it is converted to pyruvate. Glucose-6-phosphate is also substrate for the pentose phosphate shunt and the generation of glycogen only in glial cells. Pyruvate is metabolized either in the Krebs cycle after transport into the mitochondria, or converted to lactate by means of the lactate dehydrogenase. A large part of the pyruvate transported into brain mitochondria is devoted to the oxidative phosphorylation of ADP to ATP.

The energy supply to the brain is provided by blood vessels. In most brain structures, these vessels are surrounded by a blood-brain barrier which does not allow molecules to cross it and as a consequence isolates the brain from the circulatory network. Under these conditions, the energy input is partly indirect and passes partly through the cells that constitute this barrier, namely the astrocytes [9]. These cells can store energy as glycogen or transform it as lactate. This energy is released on demand, when the neurons need it [10]. This lactate is produced in astrocytes by degradation of glucose in pyruvate when the neurons need it. The lactate is then sent to neurons, which synthetize pyruvate and use it in the Krebs cycle. This role of astrocytes and lactate as the main energy substrate of neurons is still a matter of debates.

#### **4. Glucose: a signaling molecule for the brain**

In the previous part, we discussed the fact that the brain relies on glucose to function. This implies that blood glucose level must remain stable. Any decrease in blood glucose level would have immediate consequences on brain functions. Increased blood level will not have acute consequences but sustained hyperglycemia will be

**43**

**Figure 3.**

*Vm, basal membrane potential.*

*Carbohydrates and the Brain: Roles and Impact DOI: http://dx.doi.org/10.5772/intechopen.88366*

deleterious in the long term as seen in patients with uncontrolled diabetes mellitus. The brain plays a critical role in the regulation of blood glucose level to ensure wholebody glucose homeostasis. Thus, to be able to control the level of blood glucose, the brain must be able to sense any change. In this part, we will discuss the idea that glucose is more than a fueling molecule and it is able to play the role of a signaling

**Glucose-sensing neurons**: The first hypothesis that specialized cells within the brain could detect changes in glucose level originated from studies by Oomura' and Anand's groups, in which they showed that neurons within the hypothalamus had their electrical activity modified in response to intravenous injection of glucose [11, 12]. While these studies suggested that neurons able to detect glucose were present in the brain, they did not prove that glucose could directly affect these neurons since glucose was injected intravenously. Thus, later, Oomura demonstrated the presence of specialized glucose-sensing neurons in showing that the direct application of glucose in the lateral hypothalamus of rats altered the activity of specific neurons [13]. These so-called glucose-sensing neurons are now defined as cells able to adapt their electrical activity in response to changes in extracellular glucose level. By definition, glucose-excited (GE) neurons increase their electrical activity, whereas glucose-inhibited (GI) neurons decrease their activity when glucose level rises. By opposition, when glucose level decreases, GE neurons decrease their

It is important to note that glucose-sensing neurons use glucose, not only as fuel, but as a signaling molecule that modulates their electrical activity. In addition, it must be mentioned that glucose-sensing neurons directly detect changes in glucose level and not through indirect presynaptic modulation. Finally, their responses to decreased glucose level are distinct from the "run-out-of-fuel" silencing of every

**Brain glucose level**: The notion that, by definition, glucose-sensing neurons respond to physiological changes in brain glucose level raises the question of the

*Schematic representation of the electrical activity of glucose-sensing neurons in response to changes in glucose level. Glucose-excited (GE) neurons increase their electrical activity (depolarization and increased action potential frequency), whereas glucose-inhibited (GI) neurons decrease their activity (hyperpolarization and decreased firing rate) when glucose level rises. By opposition, when glucose level decreases, GE neurons decrease their electrical activity whereas GI neurons increase it. Abbreviations: glucose or glc, extracellular glucose level;* 

molecule in some neurons or brain cells called glucose-sensing cells.

electrical activity whereas GI neurons increase it (**Figure 3**).

neuron by nonphysiological low glucose levels.

*Carbohydrates and the Brain: Roles and Impact DOI: http://dx.doi.org/10.5772/intechopen.88366*

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

reversible after correction of hypoglycemia. With regard to hyperglycemia, acute situations such as ketoacidosis and hyperosmolarity can lead to a coma, with significant mortality. The chronic effects of hyperglycemia on the brain remain unclear, apart from the risk of ischemic stroke. However, microangiopathy is intimately linked to chronic hyperglycemia, and can cause irreversible diffuse vascular lesions and cerebral ischemia, resulting in cortical atrophy and diabetic encephalopathy. The brain uses glucose as its main source of energy, although it can utilize other

metabolites (mainly ketone bodies) in special situations such as fasting. It has very high energy consumption for its size, mainly due to the high energy supply needed to maintain its functions (potential difference across nerve cell membranes,

Glucose enters the brain by facilitated diffusion across the blood-brain barrier, and enters brain cells mainly via a range of glucose transporters. Most human cells import glucose by members of the GLUT (SLC2A) family of membrane transport proteins (see review [5]). Of these, GLUT1 is abundant at the BBB and in astrocytes, regulated mainly by steady-state levels of plasma glucose. GLUT2 appears to serve glucose sensors in the brain. GLUT3 ensures efficient glucose uptake by neurons. Although the brain is considered as a non-insulin-dependent organ, insulin crosses the blood-brain barrier and binds to receptors on neurons and glial cells [6]. There is controversy as to whether insulin resistance for glucose is present in the CNS, but emerging data suggest that insulin insensitivity may play an important role in the pathogenesis of obesity, type 2 diabetes, and Alzheimer's disease [7, 8]. GLUT5 and GLUT7 are present at low levels in the brain and have specificity for fructose. GLUT6 is expressed in the brain but has low affinity to glucose. Studies of mice suggest roles of GLUT8 in hippocampal neuronal proliferation. GLUT13 is a myoinositol transporter expressed primarily in the brain and is the only GLUT protein that appears to function as a proton-coupled symporter (see review [5]). Once transported into the cell, glucose is phosphorylated by a hexokinase, an enzyme with such high affinity toward glucose that it rapidly transforms glucose into glucose-6-phosphate. Glucose-6-phosphate is metabolized further, mainly in the glycolytic pathway, where it is converted to pyruvate. Glucose-6-phosphate is also substrate for the pentose phosphate shunt and the generation of glycogen only in glial cells. Pyruvate is metabolized either in the Krebs cycle after transport into the mitochondria, or converted to lactate by means of the lactate dehydrogenase. A large part of the pyruvate transported into brain mitochondria is devoted to the oxidative phosphorylation of ADP to ATP. The energy supply to the brain is provided by blood vessels. In most brain structures, these vessels are surrounded by a blood-brain barrier which does not allow molecules to cross it and as a consequence isolates the brain from the circulatory network. Under these conditions, the energy input is partly indirect and passes partly through the cells that constitute this barrier, namely the astrocytes [9]. These cells can store energy as glycogen or transform it as lactate. This energy is released on demand, when the neurons need it [10]. This lactate is produced in astrocytes by degradation of glucose in pyruvate when the neurons need it. The lactate is then sent to neurons, which synthetize pyruvate and use it in the Krebs cycle. This role of astrocytes and

transport along axons and dendrites, tissue plasticity and repair).

lactate as the main energy substrate of neurons is still a matter of debates.

In the previous part, we discussed the fact that the brain relies on glucose to function. This implies that blood glucose level must remain stable. Any decrease in blood glucose level would have immediate consequences on brain functions. Increased blood level will not have acute consequences but sustained hyperglycemia will be

**4. Glucose: a signaling molecule for the brain**

**42**

deleterious in the long term as seen in patients with uncontrolled diabetes mellitus. The brain plays a critical role in the regulation of blood glucose level to ensure wholebody glucose homeostasis. Thus, to be able to control the level of blood glucose, the brain must be able to sense any change. In this part, we will discuss the idea that glucose is more than a fueling molecule and it is able to play the role of a signaling molecule in some neurons or brain cells called glucose-sensing cells.

**Glucose-sensing neurons**: The first hypothesis that specialized cells within the brain could detect changes in glucose level originated from studies by Oomura' and Anand's groups, in which they showed that neurons within the hypothalamus had their electrical activity modified in response to intravenous injection of glucose [11, 12]. While these studies suggested that neurons able to detect glucose were present in the brain, they did not prove that glucose could directly affect these neurons since glucose was injected intravenously. Thus, later, Oomura demonstrated the presence of specialized glucose-sensing neurons in showing that the direct application of glucose in the lateral hypothalamus of rats altered the activity of specific neurons [13]. These so-called glucose-sensing neurons are now defined as cells able to adapt their electrical activity in response to changes in extracellular glucose level. By definition, glucose-excited (GE) neurons increase their electrical activity, whereas glucose-inhibited (GI) neurons decrease their activity when glucose level rises. By opposition, when glucose level decreases, GE neurons decrease their electrical activity whereas GI neurons increase it (**Figure 3**).

It is important to note that glucose-sensing neurons use glucose, not only as fuel, but as a signaling molecule that modulates their electrical activity. In addition, it must be mentioned that glucose-sensing neurons directly detect changes in glucose level and not through indirect presynaptic modulation. Finally, their responses to decreased glucose level are distinct from the "run-out-of-fuel" silencing of every neuron by nonphysiological low glucose levels.

**Brain glucose level**: The notion that, by definition, glucose-sensing neurons respond to physiological changes in brain glucose level raises the question of the

#### **Figure 3.**

*Schematic representation of the electrical activity of glucose-sensing neurons in response to changes in glucose level. Glucose-excited (GE) neurons increase their electrical activity (depolarization and increased action potential frequency), whereas glucose-inhibited (GI) neurons decrease their activity (hyperpolarization and decreased firing rate) when glucose level rises. By opposition, when glucose level decreases, GE neurons decrease their electrical activity whereas GI neurons increase it. Abbreviations: glucose or glc, extracellular glucose level; Vm, basal membrane potential.*

#### **Figure 4.**

*Extracellular brain glucose levels versus plasma glucose levels. Plasma glucose levels of about 2–4 mM (50–80 mg/dl) observed during hypoglycemia correlate brain levels of about 0.1–1 mM. Plasma levels of about 5–8 (80–120 mg/dl) are related to levels seen during meal-to-meal variation and correlate to brain levels of about 2–2.5 mM. Plasma glucose levels over 8 mM or 140 mg/dl are seen during uncontrolled hyperglycemia and correlate with brain level above 3 mM but not exceeding 4.5–5 mM. Adapted from Ref. [19].*

glucose level in the brain. The level of brain glucose is a process finely regulated by GLUT1, the glucose transporter expressed at the BBB. The high affinity of this transporter (KM = 2–3 mM) for glucose justifies the level found in the brain, which is about 30% of the blood level. Thus, several studies using glucose oxidase electrode methods or zero net flux method for microdialysis consistently indicate that physiological levels of glucose within the brain vary within a fairly tight range from 0.7 to 2.5 mM. On the other hand, extracellular brain glucose levels below 0.7 mM and above 2.5 mM are associated pathological hypo- and hyperglycemia, respectively. This is the case in all brain areas where it has been measured including the hypothalamus, the hippocampus, and striatum for instance [14–18] (**Figure 4**).

**Location and role of glucose-sensing neurons**: Most of the glucose-sensing neurons have been described in the hypothalamus in response to changes in the window between 0.1 and 5 mM, which represents the physiological changes observed in the brain (see for review [20, 21]). Nevertheless, our group found that within the arcuate nucleus (ARC), four populations of glucose-sensing neurons actually exist. We showed that the "classical" GE and GI neurons detect changes below 2.5 mM whereas so-called HGE or HGI neurons (for high-glucose-excited or -inhibited neurons) are respectively activated or inhibited by changes above 5 mM [22–25]. Interestingly, the electrical activity of HGE and HGI neurons is only changed in response to glucose change below 2.5 mM and not altered by changes in glucose level above it [22, 23]. Similarly, we found that HGE and HGI neurons only change their electrical activity in response to changes in glucose level above 5 mM but not below this level [23]. Finding these different subpopulations of glucose-sensing neurons raised the question of the actual glucose level present in the arcuate nucleus of the hypothalamus in which the BBB is fenestrated [16, 26] and suggested that, in confined areas, glucose level could be increased closer to levels found in the blood.

Not everything is known yet regarding these different populations of glucosesensing neurons. Their proportion within the different nuclei of the hypothalamus is difficult to estimate since not every study uses the same changes in glucose level. However, we could estimate that they represent around 10% of hypothalamic neurons. A question which has been poorly addressed is their interconnection. We think that some HGE or HGI neurons from the ARC may connect some VMN neurons found to be indirectly modulated to increased glucose level above

**45**

nutrient sensing.

*Carbohydrates and the Brain: Roles and Impact DOI: http://dx.doi.org/10.5772/intechopen.88366*

**Figure 5.**

5 mM [20, 23, 27]. Nevertheless, no study has directly studied their interconnection to determine whether they could work as a synchronous network. By opposition, the molecular mechanisms involved in their detection to changes in glucose level are pretty much known (see for review [20, 21]). The nature of these glucose-sensing neurons in terms of neurotransmitter expressed and released, however, is not clear for all the subpopulations [20]. Knowing better the identity of glucose-sensing neurons will be necessary to better understand the physiological functions they control, which are not fully understood yet. It is however clear that these neurons are involved in the control of food intake, thermogenesis, and glucose homeostasis (glucose tolerance, insulin secretion, and hepatic glucose production). Several studies have described that inhibiting molecular mechanisms involved in their glucose sensitivity alters some of these functions.

*pallidus; SFO, subfornical organ; VMN, ventromedial nucleus; VTA, ventral tegmental area.*

*Location of brain glucose-sensing neurons. Schematic representation of a sagittal slice of a rodent brain with different areas where glucose-sensing neurons have been found. Abbreviations: AMG, amygdala; AP, area postrema; ARC, arcuate nucleus; DMNX, dorsal motor nucleus; DMN, dorsomedial nucleus; HippoC, hippocampus; LC, locus coeruleus; LH, lateral hypothalamus; NTS, solitary nucleus; OB, olfactory bulb; PBN, parabrachial nucleus; PFC, prefrontal cortex; PO, preoptic area; PVN, paraventricular nucleus; RP, Raphe* 

Glucose-sensing neurons can be found in extra-hypothalamic areas (**Figure 5**).

**Glial cells are also able to detect glucose**: Astrocytes represent the major class of macroglial brain cells and occupy about 50% of the total brain volume. Beyond their role of structural neuronal supporting cells, astrocytes are now recognized to take an acting part in brain homeostasis and participate in increasingly large number of functions including neuronal proliferation, synaptogenesis, synaptic transmission, and neurotransmitter homeostasis as well as neuronal fueling and

To our knowledge, HGE and HGI neurons have only been found in so-called circumventricular organs, brain areas where the BBB is fenestrated including the area postrema of the hindbrain, the subfornical organ and the vascular organ of lamina terminalis. All the other brain areas where glucose-sensing have been found present neurons modulated by glucose changes below 2.5 mM glucose. This raises the question of the physiological role of these neurons in these extra-hypothalamic areas. One hypothesis is that these neurons present in different places of the brain detect decreased glucose level, which could be associated to hypoglycemia. They may play the role of detectors of energy availability and inform about a potential "crisis" since glucose is the principal fuel of neurons and its brain level needs to be finely controlled. Nevertheless, we cannot exclude that these neurons take part in physiological functions including memory, motivation olfaction, in view of their location in areas such as the hippocampus, striatum, olfactory bulb for instance. Significant work is still needed to fully understand the functions controlled by these

hypothalamic or extra-hypothalamic neurons.

*Carbohydrates and the Brain: Roles and Impact DOI: http://dx.doi.org/10.5772/intechopen.88366*

#### **Figure 5.**

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

glucose level in the brain. The level of brain glucose is a process finely regulated by GLUT1, the glucose transporter expressed at the BBB. The high affinity of this transporter (KM = 2–3 mM) for glucose justifies the level found in the brain, which is about 30% of the blood level. Thus, several studies using glucose oxidase electrode methods or zero net flux method for microdialysis consistently indicate that physiological levels of glucose within the brain vary within a fairly tight range from 0.7 to 2.5 mM. On the other hand, extracellular brain glucose levels below 0.7 mM and above 2.5 mM are associated pathological hypo- and hyperglycemia, respectively. This is the case in all brain areas where it has been measured including the hypothalamus, the hippocampus, and striatum for instance [14–18] (**Figure 4**).

*Extracellular brain glucose levels versus plasma glucose levels. Plasma glucose levels of about 2–4 mM (50–80 mg/dl) observed during hypoglycemia correlate brain levels of about 0.1–1 mM. Plasma levels of about 5–8 (80–120 mg/dl) are related to levels seen during meal-to-meal variation and correlate to brain levels of about 2–2.5 mM. Plasma glucose levels over 8 mM or 140 mg/dl are seen during uncontrolled hyperglycemia* 

*and correlate with brain level above 3 mM but not exceeding 4.5–5 mM. Adapted from Ref. [19].*

**Location and role of glucose-sensing neurons**: Most of the glucose-sensing neurons have been described in the hypothalamus in response to changes in the window between 0.1 and 5 mM, which represents the physiological changes observed in the brain (see for review [20, 21]). Nevertheless, our group found that within the arcuate nucleus (ARC), four populations of glucose-sensing neurons actually exist. We showed that the "classical" GE and GI neurons detect changes below 2.5 mM whereas so-called HGE or HGI neurons (for high-glucose-excited or -inhibited neurons) are respectively activated or inhibited by changes above 5 mM [22–25]. Interestingly, the electrical activity of HGE and HGI neurons is only changed in response to glucose change below 2.5 mM and not altered by changes in glucose level above it [22, 23]. Similarly, we found that HGE and HGI neurons only change their electrical activity in response to changes in glucose level above 5 mM but not below this level [23]. Finding these different subpopulations of glucose-sensing neurons raised the question of the actual glucose level present in the arcuate nucleus of the hypothalamus in which the BBB is fenestrated [16, 26] and suggested that, in confined areas, glucose

Not everything is known yet regarding these different populations of glucosesensing neurons. Their proportion within the different nuclei of the hypothalamus is difficult to estimate since not every study uses the same changes in glucose level. However, we could estimate that they represent around 10% of hypothalamic neurons. A question which has been poorly addressed is their interconnection. We think that some HGE or HGI neurons from the ARC may connect some VMN neurons found to be indirectly modulated to increased glucose level above

level could be increased closer to levels found in the blood.

**44**

**Figure 4.**

*Location of brain glucose-sensing neurons. Schematic representation of a sagittal slice of a rodent brain with different areas where glucose-sensing neurons have been found. Abbreviations: AMG, amygdala; AP, area postrema; ARC, arcuate nucleus; DMNX, dorsal motor nucleus; DMN, dorsomedial nucleus; HippoC, hippocampus; LC, locus coeruleus; LH, lateral hypothalamus; NTS, solitary nucleus; OB, olfactory bulb; PBN, parabrachial nucleus; PFC, prefrontal cortex; PO, preoptic area; PVN, paraventricular nucleus; RP, Raphe pallidus; SFO, subfornical organ; VMN, ventromedial nucleus; VTA, ventral tegmental area.*

5 mM [20, 23, 27]. Nevertheless, no study has directly studied their interconnection to determine whether they could work as a synchronous network. By opposition, the molecular mechanisms involved in their detection to changes in glucose level are pretty much known (see for review [20, 21]). The nature of these glucose-sensing neurons in terms of neurotransmitter expressed and released, however, is not clear for all the subpopulations [20]. Knowing better the identity of glucose-sensing neurons will be necessary to better understand the physiological functions they control, which are not fully understood yet. It is however clear that these neurons are involved in the control of food intake, thermogenesis, and glucose homeostasis (glucose tolerance, insulin secretion, and hepatic glucose production). Several studies have described that inhibiting molecular mechanisms involved in their glucose sensitivity alters some of these functions.

Glucose-sensing neurons can be found in extra-hypothalamic areas (**Figure 5**). To our knowledge, HGE and HGI neurons have only been found in so-called circumventricular organs, brain areas where the BBB is fenestrated including the area postrema of the hindbrain, the subfornical organ and the vascular organ of lamina terminalis. All the other brain areas where glucose-sensing have been found present neurons modulated by glucose changes below 2.5 mM glucose. This raises the question of the physiological role of these neurons in these extra-hypothalamic areas. One hypothesis is that these neurons present in different places of the brain detect decreased glucose level, which could be associated to hypoglycemia. They may play the role of detectors of energy availability and inform about a potential "crisis" since glucose is the principal fuel of neurons and its brain level needs to be finely controlled. Nevertheless, we cannot exclude that these neurons take part in physiological functions including memory, motivation olfaction, in view of their location in areas such as the hippocampus, striatum, olfactory bulb for instance. Significant work is still needed to fully understand the functions controlled by these hypothalamic or extra-hypothalamic neurons.

**Glial cells are also able to detect glucose**: Astrocytes represent the major class of macroglial brain cells and occupy about 50% of the total brain volume. Beyond their role of structural neuronal supporting cells, astrocytes are now recognized to take an acting part in brain homeostasis and participate in increasingly large number of functions including neuronal proliferation, synaptogenesis, synaptic transmission, and neurotransmitter homeostasis as well as neuronal fueling and nutrient sensing.

The first evidence suggesting a role of astrocytes in hypothalamic glucose-sensing was the expression of some key "glucose-sensing" protein in this cell population. Thus, our group was the first to show that GLUT2 is expressed in hypothalamic astrocytes [28–30]. Other glucose sensors such as KATP channels and glucokinase are also found in astrocytes. We also showed that increased central glucose level increases the expression of the cell activation maker c-fos in hypothalamic astrocytes [31]. More recently, studies showed that glial cells are directly glucose-sensing using primary culture. Thus, increased glucose level increases calcium waves in hypothalamic tanycytes (astrocyte-like cells present in the ventral hypothalamus) suggesting that these cells are activated by glucose as shown in neurons [32, 33]. Even though these studies started to decipher mechanisms involved in astrocyte glucose-sensing (involvement of ATP release, purinergic channels, connexins), further work is still needed to better understand the signaling pathways involved in their glucose-sensing. A question that needs to be answered is the mechanisms by which astrocytes and neurons are coupled in order to ensure brain glucosesensing. Studies from our group and others suggested that the gliotransmitter ACBP (AcetylCoA-Binding Protein), released by astrocytes in response to increased glucose level, activates pro-opiomelanocortin neurons of the arcuate nucleus, neurons highly known to control food intake, thermogenesis, and glucose homeostasis [34, 35]. ACBP is not the only gliotransmitter involved in glucose-sensing, other studies also showed the importance of ATP or lactate. Interestingly, glucose-excited neurons responding to increased glucose level are also activated by lactate [36]. Thus, in addition to be a fueling substrate for neurons, lactate, as glucose, is also considered as a signaling-like nutrient for glucose-sensing neurons. More studies are still needed to highlight other potential glucose-sensing gliotransmitter and to fully understand the role of astrocytes in brain glucose-sensing. Also, different isoforms of glucose transporters or hexokinases are expressed in other glial cells including microglia or oligodendrocytes [37]. Nevertheless, except a putative fueling role, it is not known whether these glial cell types are able to sense changes in glucose levels as neurons or astrocytes do.

#### **5. The impact of other sugars on the brain: the example of fructose**

The patterns of sugar consumption have changed considerably in recent decades. Glucose is not the only monosaccharide present in our alimentation, which can cross the intestinal barrier and be present in the bloodstream. Fructose is the other main monosaccharide we eat. Fructose is the *partner* of glucose in the sucrose we consume. In addition to its natural presence in fruit and honey, it is also present in soda, biscuits, and all sorts of processed food. Thus, while fructose consumption was <5 g/day until the 70s, it consumption has dramatically increased since and currently reaches 50–80 g/day in developed countries. In addition, the ending of European sugar quota in 2017 will likely further increase by 8–15% its intake in the next decade.

So far, the increase in fructose consumption has raised health issues regarding liver function and development of metabolic syndrome [38]. Increases in fructose consumption have paralleled the increasing prevalence of obesity, and high-fructose diets are thought to promote weight gain and insulin resistance. Thus, fructose has been pointed out by the French Anses agency as potentially harmful (saisine n° 2012-SA-0186). The agency demands "more studies aiming at understanding the effect of selective sugars including fructose, on brain functions and mental health." Thus, the impact fructose overconsumption could have on other organs or physiological functions has been somehow neglected. It has been reported that

**47**

*Carbohydrates and the Brain: Roles and Impact DOI: http://dx.doi.org/10.5772/intechopen.88366*

the consumption of this sugar.

nutritional recommendations.

**6. Conclusions**

stream and may enter organs including the brain [39].

when consumed in low amount, the intestine metabolizes fructose into glucose with almost no fructose spill over into the bloodstream. Even if spill over may happen in the portal vein, fructose will be metabolized and transformed into fatty acids by the liver. Nevertheless, when consumed in excess, fructose spills over into the blood-

The fact that the brain is fully equipped to uptake and metabolize fructose supports the concept that fructose could affect the activity of brain networks. The main fructose transporter GLUT5 and the ketohexokinase (KHK, the principal fructose-metabolizing enzyme) are expressed in the brain and at the BBB [40]. Both human and animal studies have shown that the brain reacts to high fructose intake. For instance, studies from K Page showed that fructose ingestion does activate some brain regions but which are different to the one activated by a glucose load [41, 42]. Interestingly, they showed that fructose load does not decrease the hunger sensation as compared to glucose. This would suggest that fructose does not send a satiety signal to the brain as powerful as glucose does. In support of this, studies in animal models showed that intracerebral injection of fructose stimulates food intake [43, 44]. Fructose overconsumption may also alter other brain functions including cognition and mood. Studies showed that rodents fed a high-fructose diet present memory deficits or anxiety-related behaviors [45–49]. Interestingly, it seems that the adolescence may be a more sensitive period to high fructose exposition [47, 49, 50]. This is particularly puzzling since adolescents are the population eating fructose and transformed food the most. Nevertheless, in all these animal studies with high-fructose feeding, the effect of fructose diet cannot be segregated from its impact of glucose homeostasis. It is not clear yet whether fructose may directly alter neuronal network. Many more studies need to be performed to fully understand the direct effect of fructose on brain cells and the brain functions impaired by fructose overconsumption. In addition, many other questions have not been answered yet. Can fructose be used as glucose to fuel brain cells, even though its basal blood level is extremely low? Do fructosesensing neurons or glial cells exist within the brain? These open questions must be answered rapidly in order to improve the nutritional recommendation regarding

Over the last 50 years or so, our vision of the impact of sugars on the brain has significantly evolved. Knowing for its fueling role to brain cells, glucose is also considered as a signaling molecule informing the brain of the whole-body energy status and availability thanks to the discoveries of specialized glucose-sensing neurons. The findings that not only neurons are able to sense changes in glucose level and the fact that glial or neuronal glucose sensors are present all over the brain show the importance of detecting glucose level for a proper control of energy homeostasis. Nowadays, the nutritional mutation we are facing raises other concerns. The brain would be somehow protected to glucose overconsumption in view of the transporter present at the blood-brain barrier, which is saturated around 2–2.5 mM. However, the impact on brain of the metabolic changes induced by such increase in sugar consumption is yet to be evaluated further. Which brain networks and brain functions are altered by increased sugar consumption? In addition, the change in the nature of the sugars we eat raises others questions as described here for fructose. Years of research are still needed to improve our understanding of the impact of sugars on the brain in order to propose optimal

#### *Carbohydrates and the Brain: Roles and Impact DOI: http://dx.doi.org/10.5772/intechopen.88366*

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

glucose levels as neurons or astrocytes do.

**5. The impact of other sugars on the brain: the example of fructose**

Glucose is not the only monosaccharide present in our alimentation, which can cross the intestinal barrier and be present in the bloodstream. Fructose is the other main monosaccharide we eat. Fructose is the *partner* of glucose in the sucrose we consume. In addition to its natural presence in fruit and honey, it is also present in soda, biscuits, and all sorts of processed food. Thus, while fructose consumption was <5 g/day until the 70s, it consumption has dramatically increased since and currently reaches 50–80 g/day in developed countries. In addition, the ending of European sugar quota in 2017 will likely further increase by 8–15% its intake in the

The patterns of sugar consumption have changed considerably in recent decades.

So far, the increase in fructose consumption has raised health issues regarding liver function and development of metabolic syndrome [38]. Increases in fructose consumption have paralleled the increasing prevalence of obesity, and high-fructose diets are thought to promote weight gain and insulin resistance. Thus, fructose has been pointed out by the French Anses agency as potentially harmful (saisine n° 2012-SA-0186). The agency demands "more studies aiming at understanding the effect of selective sugars including fructose, on brain functions and mental health." Thus, the impact fructose overconsumption could have on other organs or physiological functions has been somehow neglected. It has been reported that

The first evidence suggesting a role of astrocytes in hypothalamic glucose-sensing was the expression of some key "glucose-sensing" protein in this cell population. Thus, our group was the first to show that GLUT2 is expressed in hypothalamic astrocytes [28–30]. Other glucose sensors such as KATP channels and glucokinase are also found in astrocytes. We also showed that increased central glucose level increases the expression of the cell activation maker c-fos in hypothalamic astrocytes [31]. More recently, studies showed that glial cells are directly glucose-sensing using primary culture. Thus, increased glucose level increases calcium waves in hypothalamic tanycytes (astrocyte-like cells present in the ventral hypothalamus) suggesting that these cells are activated by glucose as shown in neurons [32, 33]. Even though these studies started to decipher mechanisms involved in astrocyte glucose-sensing (involvement of ATP release, purinergic channels, connexins), further work is still needed to better understand the signaling pathways involved in their glucose-sensing. A question that needs to be answered is the mechanisms by which astrocytes and neurons are coupled in order to ensure brain glucosesensing. Studies from our group and others suggested that the gliotransmitter ACBP (AcetylCoA-Binding Protein), released by astrocytes in response to increased glucose level, activates pro-opiomelanocortin neurons of the arcuate nucleus, neurons highly known to control food intake, thermogenesis, and glucose homeostasis [34, 35]. ACBP is not the only gliotransmitter involved in glucose-sensing, other studies also showed the importance of ATP or lactate. Interestingly, glucose-excited neurons responding to increased glucose level are also activated by lactate [36]. Thus, in addition to be a fueling substrate for neurons, lactate, as glucose, is also considered as a signaling-like nutrient for glucose-sensing neurons. More studies are still needed to highlight other potential glucose-sensing gliotransmitter and to fully understand the role of astrocytes in brain glucose-sensing. Also, different isoforms of glucose transporters or hexokinases are expressed in other glial cells including microglia or oligodendrocytes [37]. Nevertheless, except a putative fueling role, it is not known whether these glial cell types are able to sense changes in

**46**

next decade.

when consumed in low amount, the intestine metabolizes fructose into glucose with almost no fructose spill over into the bloodstream. Even if spill over may happen in the portal vein, fructose will be metabolized and transformed into fatty acids by the liver. Nevertheless, when consumed in excess, fructose spills over into the bloodstream and may enter organs including the brain [39].

The fact that the brain is fully equipped to uptake and metabolize fructose supports the concept that fructose could affect the activity of brain networks. The main fructose transporter GLUT5 and the ketohexokinase (KHK, the principal fructose-metabolizing enzyme) are expressed in the brain and at the BBB [40]. Both human and animal studies have shown that the brain reacts to high fructose intake. For instance, studies from K Page showed that fructose ingestion does activate some brain regions but which are different to the one activated by a glucose load [41, 42]. Interestingly, they showed that fructose load does not decrease the hunger sensation as compared to glucose. This would suggest that fructose does not send a satiety signal to the brain as powerful as glucose does. In support of this, studies in animal models showed that intracerebral injection of fructose stimulates food intake [43, 44]. Fructose overconsumption may also alter other brain functions including cognition and mood. Studies showed that rodents fed a high-fructose diet present memory deficits or anxiety-related behaviors [45–49]. Interestingly, it seems that the adolescence may be a more sensitive period to high fructose exposition [47, 49, 50]. This is particularly puzzling since adolescents are the population eating fructose and transformed food the most. Nevertheless, in all these animal studies with high-fructose feeding, the effect of fructose diet cannot be segregated from its impact of glucose homeostasis. It is not clear yet whether fructose may directly alter neuronal network. Many more studies need to be performed to fully understand the direct effect of fructose on brain cells and the brain functions impaired by fructose overconsumption. In addition, many other questions have not been answered yet. Can fructose be used as glucose to fuel brain cells, even though its basal blood level is extremely low? Do fructosesensing neurons or glial cells exist within the brain? These open questions must be answered rapidly in order to improve the nutritional recommendation regarding the consumption of this sugar.

## **6. Conclusions**

Over the last 50 years or so, our vision of the impact of sugars on the brain has significantly evolved. Knowing for its fueling role to brain cells, glucose is also considered as a signaling molecule informing the brain of the whole-body energy status and availability thanks to the discoveries of specialized glucose-sensing neurons. The findings that not only neurons are able to sense changes in glucose level and the fact that glial or neuronal glucose sensors are present all over the brain show the importance of detecting glucose level for a proper control of energy homeostasis. Nowadays, the nutritional mutation we are facing raises other concerns. The brain would be somehow protected to glucose overconsumption in view of the transporter present at the blood-brain barrier, which is saturated around 2–2.5 mM. However, the impact on brain of the metabolic changes induced by such increase in sugar consumption is yet to be evaluated further. Which brain networks and brain functions are altered by increased sugar consumption? In addition, the change in the nature of the sugars we eat raises others questions as described here for fructose. Years of research are still needed to improve our understanding of the impact of sugars on the brain in order to propose optimal nutritional recommendations.

## **Acknowledgements**

The authors are thankful to C. Bosh-Bouju and S. Layé for the invitation to write a chapter in the book they are editing.

## **Conflict of interest**

The authors declare no conflict of interest.

## **Author details**

Xavier Fioramonti1 \* and Luc Pénicaud<sup>2</sup>

1 Université de Bordeaux, INRA, Bordeaux INP, NutriNeuro, UMR 1286, Bordeaux, France

2 UMR STROMALab, Université de Toulouse, CNRS ERL5311, EFS, INP-ENVT, Inserm U1031, UPS, Toulouse, France

\*Address all correspondence to: xavier.fioramonti@inra.fr

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**49**

*Carbohydrates and the Brain: Roles and Impact DOI: http://dx.doi.org/10.5772/intechopen.88366*

Dienel GA, Meisel A. Sugar for the brain: The role of glucose in physiological and pathological brain function. Trends in Neurosciences. 2013;**36**:587-597. DOI:

insulin/IGF signaling and reduced neuroinflammation with T3D-959 in an experimental model of sporadic Alzheimer's disease. Journal of Alzheimer's Disease. 2017;**55**:849-864.

DOI: 10.3233/JAD-160656

s41593-018-0286-y

jcbfm.2011.149

1964;**143**:484-485

1964;**207**:1146-1154

[9] Garcia-Caceres C, Balland E,

Prevot V, Luquet S, Woods SC, Koch M, et al. Role of astrocytes, microglia, and tanycytes in brain control of systemic metabolism. Nature Neuroscience. 2019;**22**:7-14. DOI: 10.1038/

[10] Pellerin L, Magistretti PJ. Sweet sixteen for ANLS. Journal of

Cerebral Blood Flow & Metabolism. 2012;**32**:1152-1166. DOI: 10.1038/

[11] Oomura Y, Kimura K, Ooyama H, Maeo T, Iki M, Kuniyoshi N. Reciprocal activities of the ventromedial and lateral hypothalamic area of cats. Science.

[12] Anand BK, Chhina GS, Sharma KN, Dua S, Singh B. Activity of single neurons in the hypothalamic feeding centers: Effect of glucose. American Journal of Physiology-Legacy Content.

[13] Oomura Y, Ooyama H, Sugimori M,

Nakamura T, Yamada Y. Glucose inhibition of the glucose-sensitive neurone in the rat lateral hypothalamus.

[14] de Vries MG, Arseneau LM, Lawson ME, Beverly JL. Extracellular glucose in rat ventromedial hypothalamus during acute and recurrent hypoglycemia.

Diabetes. 2003;**52**:2767-2773

[15] Dunn-Meynell AA, Sanders NM, Compton D, Becker TC, Eiki J, Zhang BB, et al. Relationship among brain and blood glucose levels and spontaneous and glucoprivic feeding. Journal of

Nature. 1974;**247**:284-286

[1] Mergenthaler P, Lindauer U,

[2] Levin BE. Metabolic sensing neurons and the control of energy homeostasis. Physiology & Behavior. 2006;**89**:486-489. DOI: 10.1016/j.

[3] Penicaud L, Leloup C, Lorsignol A, Alquier T, Guillod E. Brain glucose sensing mechanism and glucose homeostasis. Current Opinion in Clinical Nutrition and Metabolic Care.

10.1016/j.tins.2013.07.001

physbeh.2006.07.003

2002;**5**:539-543

ajpendo.00712.2009

tem.2012.11.004

physrev.00032.2015

Didsbury J. Improved brain

[4] Bentsen MA, Mirzadeh Z, Schwartz MW. Revisiting how the brain senses glucose-and why. Cell Metabolism. 2019;**29**:11-17. DOI: 10.1016/j.cmet.2018.11.001

[5] Thorens B, Mueckler M. Glucose transporters in the 21st Century. American Journal of Physiology-Endocrinology and Metabolism. 2010;**298**:E141-E145. DOI: 10.1152/

[6] Vogt MC, Bruning JC. CNS insulin signaling in the control of energy homeostasis and glucose metabolism— From embryo to old age. Trends in Endocrinology and Metabolism. 2013;**24**:76-84. DOI: 10.1016/j.

[7] Kullmann S, Heni M, Hallschmid M, Fritsche A, Preissl H, Haring HU. Brain insulin resistance at the crossroads of metabolic and cognitive disorders in humans. Physiological Reviews. 2016;**96**:1169-1209. DOI: 10.1152/

[8] de la Monte SM, Tong M, Schiano I,

**References**

*Carbohydrates and the Brain: Roles and Impact DOI: http://dx.doi.org/10.5772/intechopen.88366*

## **References**

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

The authors are thankful to C. Bosh-Bouju and S. Layé for the invitation to write

**Acknowledgements**

**Conflict of interest**

a chapter in the book they are editing.

The authors declare no conflict of interest.

**48**

**Author details**

France

Xavier Fioramonti1

Inserm U1031, UPS, Toulouse, France

provided the original work is properly cited.

\* and Luc Pénicaud<sup>2</sup>

\*Address all correspondence to: xavier.fioramonti@inra.fr

1 Université de Bordeaux, INRA, Bordeaux INP, NutriNeuro, UMR 1286, Bordeaux,

2 UMR STROMALab, Université de Toulouse, CNRS ERL5311, EFS, INP-ENVT,

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

[1] Mergenthaler P, Lindauer U, Dienel GA, Meisel A. Sugar for the brain: The role of glucose in physiological and pathological brain function. Trends in Neurosciences. 2013;**36**:587-597. DOI: 10.1016/j.tins.2013.07.001

[2] Levin BE. Metabolic sensing neurons and the control of energy homeostasis. Physiology & Behavior. 2006;**89**:486-489. DOI: 10.1016/j. physbeh.2006.07.003

[3] Penicaud L, Leloup C, Lorsignol A, Alquier T, Guillod E. Brain glucose sensing mechanism and glucose homeostasis. Current Opinion in Clinical Nutrition and Metabolic Care. 2002;**5**:539-543

[4] Bentsen MA, Mirzadeh Z, Schwartz MW. Revisiting how the brain senses glucose-and why. Cell Metabolism. 2019;**29**:11-17. DOI: 10.1016/j.cmet.2018.11.001

[5] Thorens B, Mueckler M. Glucose transporters in the 21st Century. American Journal of Physiology-Endocrinology and Metabolism. 2010;**298**:E141-E145. DOI: 10.1152/ ajpendo.00712.2009

[6] Vogt MC, Bruning JC. CNS insulin signaling in the control of energy homeostasis and glucose metabolism— From embryo to old age. Trends in Endocrinology and Metabolism. 2013;**24**:76-84. DOI: 10.1016/j. tem.2012.11.004

[7] Kullmann S, Heni M, Hallschmid M, Fritsche A, Preissl H, Haring HU. Brain insulin resistance at the crossroads of metabolic and cognitive disorders in humans. Physiological Reviews. 2016;**96**:1169-1209. DOI: 10.1152/ physrev.00032.2015

[8] de la Monte SM, Tong M, Schiano I, Didsbury J. Improved brain

insulin/IGF signaling and reduced neuroinflammation with T3D-959 in an experimental model of sporadic Alzheimer's disease. Journal of Alzheimer's Disease. 2017;**55**:849-864. DOI: 10.3233/JAD-160656

[9] Garcia-Caceres C, Balland E, Prevot V, Luquet S, Woods SC, Koch M, et al. Role of astrocytes, microglia, and tanycytes in brain control of systemic metabolism. Nature Neuroscience. 2019;**22**:7-14. DOI: 10.1038/ s41593-018-0286-y

[10] Pellerin L, Magistretti PJ. Sweet sixteen for ANLS. Journal of Cerebral Blood Flow & Metabolism. 2012;**32**:1152-1166. DOI: 10.1038/ jcbfm.2011.149

[11] Oomura Y, Kimura K, Ooyama H, Maeo T, Iki M, Kuniyoshi N. Reciprocal activities of the ventromedial and lateral hypothalamic area of cats. Science. 1964;**143**:484-485

[12] Anand BK, Chhina GS, Sharma KN, Dua S, Singh B. Activity of single neurons in the hypothalamic feeding centers: Effect of glucose. American Journal of Physiology-Legacy Content. 1964;**207**:1146-1154

[13] Oomura Y, Ooyama H, Sugimori M, Nakamura T, Yamada Y. Glucose inhibition of the glucose-sensitive neurone in the rat lateral hypothalamus. Nature. 1974;**247**:284-286

[14] de Vries MG, Arseneau LM, Lawson ME, Beverly JL. Extracellular glucose in rat ventromedial hypothalamus during acute and recurrent hypoglycemia. Diabetes. 2003;**52**:2767-2773

[15] Dunn-Meynell AA, Sanders NM, Compton D, Becker TC, Eiki J, Zhang BB, et al. Relationship among brain and blood glucose levels and spontaneous and glucoprivic feeding. Journal of

Neuroscience. 2009;**29**:7015-7022. DOI: 10.1523/JNEUROSCI.0334-09.2009

[16] Langlet F, Levin BE, Luquet S, Mazzone M, Messina A, Dunn-Meynell AA, et al. Tanycytic VEGF-A boosts blood-hypothalamus barrier plasticity and access of metabolic signals to the arcuate nucleus in response to fasting. Cell Metabolism. 2013;**17**:607-617. DOI: 10.1016/j.cmet.2013.03.004

[17] McNay EC, Gold PE. Extracellular glucose concentrations in the rat hippocampus measured by zeronet-flux: Effects of microdialysis flow rate, strain, and age. Journal of Neurochemistry. 1999;**72**:785-790

[18] McNay EC, McCarty RC, Gold PE. Fluctuations in brain glucose concentration during behavioral testing: Dissociations between brain areas and between brain and blood. Neurobiology of Learning and Memory. 2001;**75**:325-337

[19] Routh VH. Glucose-sensing neurons: Are they physiologically relevant? Physiology & Behavior. 2002;**76**:403-413. DOI: S0031938402007618 [pii]

[20] Fioramonti X, Chretien C, Leloup C, Penicaud L. Recent advances in the cellular and molecular mechanisms of hypothalamic neuronal glucose detection. Frontiers in Physiology. 2017;**8**:875. DOI: 10.3389/ fphys.2017.00875

[21] Routh VH, Hao L, Santiago AM, Sheng Z, Zhou C. Hypothalamic glucose sensing: Making ends meet. Frontiers in Systems Neuroscience. 2014;**8**:236. DOI: 10.3389/fnsys.2014.00236

[22] Wang R, Liu X, Hentges ST, Dunn-Meynell AA, Levin BE, Wang W, et al. The regulation of glucose-excited neurons in the hypothalamic arcuate nucleus by glucose and feeding-relevant peptides. Diabetes. 2004;**53**:1959-1965

[23] Fioramonti X, Lorsignol A, Taupignon A, Penicaud L. A new ATP-sensitive K+ channel-independent mechanism is involved in glucoseexcited neurons of mouse arcuate nucleus. Diabetes. 2004;**53**:2767-2775. DOI: 53/11/2767 [pii]

[24] Penicaud L, Leloup C, Fioramonti X, Lorsignol A, Benani A. Brain glucose sensing: A subtle mechanism. Current Opinion in Clinical Nutrition and Metabolic Care. 2006;**9**:458-462

[25] Chretien C, Fenech C, Lienard F, Grall S, Chevalier C, Chaudy S, et al. Transient receptor potential canonical 3 (TRPC3) channels are required for hypothalamic glucose detection and energy homeostasis. Diabetes. 2017;**66**:314-324. DOI: 10.2337/ db16-1114

[26] Ciofi P. The arcuate nucleus as a circumventricular organ in the mouse. Neuroscience Letters. 2011;**487**:187-190. DOI: 10.1016/j.neulet.2010.10.019

[27] Song Z, Levin BE, McArdle JJ, Bakhos N, Routh VH. Convergence of pre- and postsynaptic influences on glucosensing neurons in the ventromedial hypothalamic nucleus. Diabetes. 2001;**50**:2673-2681

[28] Arluison M, Quignon M, Nguyen P, Thorens B, Leloup C, Penicaud L. Distribution and anatomical localization of the glucose transporter 2 (GLUT2) in the adult rat brain—An immunohistochemical study. Journal of Chemical Neuroanatomy. 2004;**28**:117-136

[29] Arluison M, Quignon M, Thorens B, Leloup C, Penicaud L. Immunocytochemical localization of the glucose transporter 2 (GLUT2) in the adult rat brain. II. Electron microscopic study. Journal of Chemical Neuroanatomy. 2004;**28**:137-146

[30] Leloup C, Arluison M, Lepetit N, Cartier N, Marfaing-Jallat P, Ferre P,

**51**

*Carbohydrates and the Brain: Roles and Impact DOI: http://dx.doi.org/10.5772/intechopen.88366*

et al. Glucose transporter 2 (GLUT 2): Expression in specific brain nuclei. Brain Research. 1994;**638**:221-226

revealed by deep single-cell RNA sequencing. Neuron. 2019;**101**:207-223. e10. DOI: 10.1016/j.neuron.2018.12.006

[38] Tappy L. Fructose metabolism and noncommunicable diseases: Recent findings and new research perspectives. Current Opinion in Clinical Nutrition and Metabolic Care. 2018;**21**:214-222. DOI: 10.1097/

[39] Jang C, Hui S, Lu W, Cowan AJ, Morscher RJ, Lee G, et al. The small intestine converts dietary fructose into glucose and organic acids. Cell Metabolism. 2018;**27**:351-361.e3. DOI:

[40] Oppelt SA, Zhang W, Tolan DR. Specific regions of the brain are capable of fructose metabolism. Brain Research. 2017;**1657**:312-322. DOI: 10.1016/j.

[41] Page KA, Chan O, Arora J, Belfort-Deaguiar R, Dzuira J, Roehmholdt B, et al. Effects of fructose vs glucose on regional cerebral blood flow in brain regions involved with appetite and reward pathways. JAMA. 2013;**309**:63- 70. DOI: 10.1001/jama.2012.116975

[42] Luo S, Monterosso JR, Sarpelleh K, Page KA. Differential effects of fructose versus glucose on brain and appetitive responses to food cues and decisions for food rewards. Proceedings of the National Academy of Sciences. 2015;**112**:6509-6514. DOI: 10.1073/

[43] Miller CC, Martin RJ, Whitney ML, Edwards GL. Intracerebroventricular injection of fructose stimulates feeding in rats. Nutritional

Neuroscience. 2002;**5**:359-362. DOI: 10.1080/1028415021000033839

[44] Cha SH, Wolfgang M, Tokutake Y, Chohnan S, Lane MD. Differential effects of central fructose and glucose on hypothalamic malonyl-CoA and

MCO.0000000000000460

10.1016/j.cmet.2017.12.016

brainres.2016.12.022

pnas.1503358112

[31] Guillod-Maximin E, Lorsignol A,

intracarotid glucose injection towards the brain induces specific c-fos activation in hypothalamic nuclei: Involvement of astrocytes in cerebral glucose-sensing in rats. Journal of Neuroendocrinology. 2004;**16**:464-471. DOI: 10.1111/j.1365-2826.2004.01185.x

[32] Frayling C, Britton R, Dale N. ATPmediated glucosensing by hypothalamic tanycytes. The Journal of Physiology. 2011;**589**:2275-2286. DOI: 10.1113/

[33] Orellana JA, Saez PJ, Cortes-Campos C, Elizondo RJ, Shoji KF, Contreras-Duarte S, et al. Glucose increases intracellular free Ca(2+) in tanycytes via ATP released through connexin 43 hemichannels. Glia. 2012;**60**:53-68. DOI:

[34] Bouyakdan K, Martin H, Lienard F, Budry L, Taib B, Rodaros D, et al. The gliotransmitter ACBP controls feeding and energy homeostasis via the melanocortin system. Journal of Clinical Investigation. 2019;**130**:2417-2430. DOI:

[35] Lanfray D, Arthaud S, Ouellet J, Compere V, Do Rego JL, Leprince J, et al. Gliotransmission and brain glucose sensing: Critical role of endozepines. Diabetes. 2013;**62**:801-810. DOI:

[36] Yang XJ, Kow LM, Funabashi T, Mobbs CV. Hypothalamic glucose sensor: Similarities to and differences from pancreatic beta-cell mechanisms.

Diabetes. 1999;**48**:1763-1772

[37] Li Q, Cheng Z, Zhou L, Darmanis S, Neff NF, Okamoto J, et al. Developmental heterogeneity of microglia and brain myeloid cells

Alquier T, Penicaud L. Acute

jphysiol.2010.202051

10.1002/glia.21246

10.1172/JCI123454

10.2337/db11-0785

*Carbohydrates and the Brain: Roles and Impact DOI: http://dx.doi.org/10.5772/intechopen.88366*

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

[23] Fioramonti X, Lorsignol A, Taupignon A, Penicaud L. A new ATP-sensitive K+ channel-independent mechanism is involved in glucoseexcited neurons of mouse arcuate nucleus. Diabetes. 2004;**53**:2767-2775.

[24] Penicaud L, Leloup C, Fioramonti X, Lorsignol A, Benani A. Brain glucose sensing: A subtle mechanism. Current Opinion in Clinical Nutrition and Metabolic Care. 2006;**9**:458-462

[25] Chretien C, Fenech C, Lienard F, Grall S, Chevalier C, Chaudy S, et al. Transient receptor potential canonical 3 (TRPC3) channels are required for hypothalamic glucose detection and energy homeostasis. Diabetes. 2017;**66**:314-324. DOI: 10.2337/

[26] Ciofi P. The arcuate nucleus as a circumventricular organ in the mouse. Neuroscience Letters. 2011;**487**:187-190. DOI: 10.1016/j.neulet.2010.10.019

[27] Song Z, Levin BE, McArdle JJ, Bakhos N, Routh VH. Convergence of pre- and postsynaptic influences on glucosensing neurons in the ventromedial hypothalamic nucleus.

[28] Arluison M, Quignon M, Nguyen P, Thorens B, Leloup C, Penicaud L. Distribution and anatomical

localization of the glucose transporter 2 (GLUT2) in the adult rat brain—An immunohistochemical study. Journal of Chemical Neuroanatomy. 2004;**28**:117-136

[30] Leloup C, Arluison M, Lepetit N, Cartier N, Marfaing-Jallat P, Ferre P,

Diabetes. 2001;**50**:2673-2681

[29] Arluison M, Quignon M, Thorens B, Leloup C, Penicaud L. Immunocytochemical localization of the glucose transporter 2 (GLUT2) in the adult rat brain. II. Electron microscopic study. Journal of Chemical Neuroanatomy. 2004;**28**:137-146

DOI: 53/11/2767 [pii]

db16-1114

Neuroscience. 2009;**29**:7015-7022. DOI: 10.1523/JNEUROSCI.0334-09.2009

[16] Langlet F, Levin BE, Luquet S, Mazzone M, Messina A, Dunn-Meynell AA, et al. Tanycytic VEGF-A boosts blood-hypothalamus barrier plasticity and access of metabolic signals to the arcuate nucleus in response to fasting. Cell Metabolism. 2013;**17**:607-617. DOI:

10.1016/j.cmet.2013.03.004

[17] McNay EC, Gold PE. Extracellular glucose concentrations in the rat hippocampus measured by zeronet-flux: Effects of microdialysis flow rate, strain, and age. Journal of Neurochemistry. 1999;**72**:785-790

[18] McNay EC, McCarty RC, Gold PE.

Fluctuations in brain glucose concentration during behavioral testing: Dissociations between brain areas and between brain and blood. Neurobiology of Learning and Memory.

[19] Routh VH. Glucose-sensing neurons: Are they physiologically

Behavior. 2002;**76**:403-413. DOI:

[20] Fioramonti X, Chretien C, Leloup C, Penicaud L. Recent

glucose detection. Frontiers in Physiology. 2017;**8**:875. DOI: 10.3389/

10.3389/fnsys.2014.00236

fphys.2017.00875

advances in the cellular and molecular mechanisms of hypothalamic neuronal

[21] Routh VH, Hao L, Santiago AM, Sheng Z, Zhou C. Hypothalamic glucose sensing: Making ends meet. Frontiers in Systems Neuroscience. 2014;**8**:236. DOI:

[22] Wang R, Liu X, Hentges ST, Dunn-Meynell AA, Levin BE, Wang W, et al. The regulation of glucose-excited neurons in the hypothalamic arcuate nucleus by glucose and feeding-relevant peptides. Diabetes. 2004;**53**:1959-1965

relevant? Physiology &

S0031938402007618 [pii]

2001;**75**:325-337

**50**

et al. Glucose transporter 2 (GLUT 2): Expression in specific brain nuclei. Brain Research. 1994;**638**:221-226

[31] Guillod-Maximin E, Lorsignol A, Alquier T, Penicaud L. Acute intracarotid glucose injection towards the brain induces specific c-fos activation in hypothalamic nuclei: Involvement of astrocytes in cerebral glucose-sensing in rats. Journal of Neuroendocrinology. 2004;**16**:464-471. DOI: 10.1111/j.1365-2826.2004.01185.x

[32] Frayling C, Britton R, Dale N. ATPmediated glucosensing by hypothalamic tanycytes. The Journal of Physiology. 2011;**589**:2275-2286. DOI: 10.1113/ jphysiol.2010.202051

[33] Orellana JA, Saez PJ, Cortes-Campos C, Elizondo RJ, Shoji KF, Contreras-Duarte S, et al. Glucose increases intracellular free Ca(2+) in tanycytes via ATP released through connexin 43 hemichannels. Glia. 2012;**60**:53-68. DOI: 10.1002/glia.21246

[34] Bouyakdan K, Martin H, Lienard F, Budry L, Taib B, Rodaros D, et al. The gliotransmitter ACBP controls feeding and energy homeostasis via the melanocortin system. Journal of Clinical Investigation. 2019;**130**:2417-2430. DOI: 10.1172/JCI123454

[35] Lanfray D, Arthaud S, Ouellet J, Compere V, Do Rego JL, Leprince J, et al. Gliotransmission and brain glucose sensing: Critical role of endozepines. Diabetes. 2013;**62**:801-810. DOI: 10.2337/db11-0785

[36] Yang XJ, Kow LM, Funabashi T, Mobbs CV. Hypothalamic glucose sensor: Similarities to and differences from pancreatic beta-cell mechanisms. Diabetes. 1999;**48**:1763-1772

[37] Li Q, Cheng Z, Zhou L, Darmanis S, Neff NF, Okamoto J, et al. Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing. Neuron. 2019;**101**:207-223. e10. DOI: 10.1016/j.neuron.2018.12.006

[38] Tappy L. Fructose metabolism and noncommunicable diseases: Recent findings and new research perspectives. Current Opinion in Clinical Nutrition and Metabolic Care. 2018;**21**:214-222. DOI: 10.1097/ MCO.0000000000000460

[39] Jang C, Hui S, Lu W, Cowan AJ, Morscher RJ, Lee G, et al. The small intestine converts dietary fructose into glucose and organic acids. Cell Metabolism. 2018;**27**:351-361.e3. DOI: 10.1016/j.cmet.2017.12.016

[40] Oppelt SA, Zhang W, Tolan DR. Specific regions of the brain are capable of fructose metabolism. Brain Research. 2017;**1657**:312-322. DOI: 10.1016/j. brainres.2016.12.022

[41] Page KA, Chan O, Arora J, Belfort-Deaguiar R, Dzuira J, Roehmholdt B, et al. Effects of fructose vs glucose on regional cerebral blood flow in brain regions involved with appetite and reward pathways. JAMA. 2013;**309**:63- 70. DOI: 10.1001/jama.2012.116975

[42] Luo S, Monterosso JR, Sarpelleh K, Page KA. Differential effects of fructose versus glucose on brain and appetitive responses to food cues and decisions for food rewards. Proceedings of the National Academy of Sciences. 2015;**112**:6509-6514. DOI: 10.1073/ pnas.1503358112

[43] Miller CC, Martin RJ, Whitney ML, Edwards GL. Intracerebroventricular injection of fructose stimulates feeding in rats. Nutritional Neuroscience. 2002;**5**:359-362. DOI: 10.1080/1028415021000033839

[44] Cha SH, Wolfgang M, Tokutake Y, Chohnan S, Lane MD. Differential effects of central fructose and glucose on hypothalamic malonyl-CoA and

food intake. Proceedings of the National Academy of Sciences. 2008;**105**: 16871-16875. DOI: 10.1073/ pnas.0809255105

[45] Lowette K, Roosen L, Tack J, Vanden Berghe P. Effects of high-fructose diets on central appetite signaling and cognitive function. Frontiers in Nutrition. 2015;**2**:5. DOI: 10.3389/fnut.2015.00005

[46] Wu HW, Ren LF, Zhou X, Han DW. A high-fructose diet induces hippocampal insulin resistance and exacerbates memory deficits in male Sprague-Dawley rats. Nutritional Neuroscience. 2015;**18**:323-328. DOI: 10.1179/1476830514Y.0000000133

[47] Harrell CS, Burgado J, Kelly SD, Johnson ZP, Neigh GN. Highfructose diet during periadolescent development increases depressivelike behavior and remodels the hypothalamic transcriptome in male rats. Psychoneuroendocrinology. 2015;**62**:252-264. DOI: 10.1016/j. psyneuen.2015.08.025

[48] Hsu TM, Konanur VR, Taing L, Usui R, Kayser BD, Goran MI, et al. Effects of sucrose and high fructose corn syrup consumption on spatial memory function and hippocampal neuroinflammation in adolescent rats. Hippocampus. 2015;**25**:227-239. DOI: 10.1002/hipo.22368

[49] Reddy BR, Maitra S, Jhelum P, Kumar KP, Bagul PK, Kaur G, et al. Sirtuin 1 and 7 mediate resveratrolinduced recovery from hyper-anxiety in high-fructose-fed prediabetic rats. Journal of Biosciences. 2016;**41**:407-417

[50] Zemdegs J, Quesseveur G, Jarriault D, Penicaud L, Fioramonti X, Guiard BP. High-fat diet-induced metabolic disorders impairs 5-HT function and anxiety-like behavior in mice. British Journal of Pharmacology. 2016;**173**:2095-2110. DOI: 10.1111/ bph.13343

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Section 4

Diet and Autophagy

in the Brain

Section 4
