**1. Introduction**

"Eating", especially glucose ingestion is essential for brain function. When we get tired either physically or mentally, we may want "sweet stuff". Some people prefer "fatty food". These unconscious impulses imply fundamental roles of glucose and fatty acid in the brain. The human brain is a complex, organized organ consisting of numerous cell types including neurons and glial cells [1, 2]. In addition, the microvasculature, which supplies oxygen and glucose, is also an essential component [3]. The human adult brain weighs 1.4 kg, or approximately 2% of the body weight, and consumes 20% of the total oxygen consumption and 25% of the glucose consumption in the body (**Figure 1**) [4, 5]. Brain function mainly consists of intellectual information processing, which is based on the generation of action potentials resulting from ionic flux across the cellular membrane. The ratio of the cerebral metabolic rate of oxygen (CMRoxy) to glucose (CMRglc) consumption

#### **Figure 1.**

*Cerebral metabolic rate of glucose (CMRglc) and oxygen (CMRoxy) in human adults (adapted from [4]).*

is approximately 6, implying the complete oxidation of one molecule of glucose (6 carbon molecules) for every 6 molecules of oxygen, producing CO2 and H2O (**Figure 1**) [4, 5]. The first step in glucose metabolism is glycolysis, which generates 2 ATPs; pyruvate/lactate is the end-product of glycolysis, and this product then enters the tricarboxylic acid (TCA) cycle, where ATP is produced more efficiently (resulting in 36 ATPs). Continuous ATP production is essential to generate action potentials, maintaining consciousness as well as intellectual function. Surprisingly, however, ATP production in the brain is solely dependent on glucose and oxygen as energy substrates [4, 5]. Moreover, these essential energy substrates must be supplied from outside of the brain through the microvasculature, since there is virtually no storage of glucose or oxygen in the brain. As a result, even a short period of cessation in cerebral blood flow (CBF) induces an immediate impairment of brain function [6]. Longer periods of ischemia cause irreversible damage to brain cells, making the restoration of function in stroke patients difficult even after vigorous rehabilitation [6, 7].

Regarding the maintenance and restoration of brain function, the topic of synaptic plasticity is essential. The theoretical basis of the beneficial effects of physical exercise on brain function relies on the facilitation of synaptic transmission and plasticity. Brain-derived neurotrophic factor (BDNF) plays a pivotal role in maintaining the neural network, improving its function, and restoring the network after damage [8, 9]. BDNF is a neurotrophic factor that was identified in the pig brain for the first time in 1982 [9]. BDNF, which is produced in both neurons and glial cells, improves a wide variety of neuronal functions including both motor functions and memory [8, 9]. Physical exercise does, indeed, improve not only motor function, but also mental function [10–12]. Unfortunately, however, the exact mechanism by which physical exercise induces BDNF production in the brain has not yet been elucidated. Recently, two nutrient molecules that are closely related to brain energy metabolism have become points of focus: lactate [13, 14] and beta-hydroxybutyrate (BHB) [15, 16]. The former is an end-product of glycolysis, and the latter is a type of ketone body, which are metabolites of fatty acid produced through beta-oxidation. Importantly, the concentrations of both lactate and BHB have been widely recognized as being elevated after exercise as a result of increases in their production by skeletal muscle and in the liver, respectively. Furthermore, both lactate and BHB are transported into the brain via monocarboxylate transporters (MCTs) (**Figure 2**) [17]. Therefore, lactate and BHB are also cable of acting as signal molecules resulting in BDNF production in the brain.

*Lactate and Ketone Bodies Act as Energy Substrates as Well as Signal Molecules in the Brain DOI: http://dx.doi.org/10.5772/intechopen.97035*

#### **Figure 2.**

*Physical activity, brain, muscle, liver, and BDNF: hypothetical model 1. BDNF, brain-derived neurotrophic factor; MCT1, monocarboxylate transporter 1 (expressed on brain microvessels).*

As described above, brain energy metabolism is solely dependent on exogenous glucose and oxygen supplied from outside the brain under normal physiological conditions [4, 5]. Importantly, however, it has also long been known that exogenous lactate and BHB can fuel the brain as alternative energy substrates under non-physiological conditions such as starvation, insulin-resistance and so on [4, 5]. Lactate enters the TCA cycle of the neurons after the conversion of acetyl-CoA by the pyruvate dehydrogenase complex (PDHC), while BHB can enter the TCA cycle directly without the action of PDHC (**Figure 3**) [4, 5]. These mechanisms imply that the exercise-induced production of lactate and BHB provides (1) energy substrates for the short-term maintenance of brain function, and (2) signal molecules capable of inducing BDNF production in the brain for the long-term maintenance of brain plasticity.

#### **Figure 3.**

*Transportation and metabolic pathway of lactate and ketone bodies (β-hydroxybutyrate and acetoacetate) into neural cells. MCT, monocarboxylate transporter; Glut, glucose transporter; TCA, tricarboxylic acid; PDHC, pyruvate dehydrogenase complex.*

#### **Figure 4.**

*Physical activity, brain (neurons and glial cells), muscle, liver, and BDNF: hypothetical model 2. BDNF, brain-derived neurotrophic factor; MCT2, monocarboxylate transporter 2 (expressed on neurons), MCT4, monocarboxylate transporter 4 (expressed on astroglia).*

The brain, muscle, and liver therefore compose a metabolic network that is linked through physical exercise. Of note, physical exercise (voluntary movement) is initiated by neuronal excitation (**Figure 2**) [4, 5]. Generally, the functional activation of the brain increases both local CMRglc and local CMRoxy to produce more ATPs. Under normal resting conditions, neither lactate nor BHB is present in the blood in sufficient quantities to be transported into the brain because of the slow transportation kinetics of MCTs [4, 5]. As a result, their roles as energy substrates for the brain seem to be limited. Importantly, however, the brain itself, or more exactly its astroglia, can produce both lactate and BHB upon neuronal excitation (**Figure 4**) [3–5]. Our research has focused on the metabolic compartmentalization between neurons and glial cells [18–27], revealing that astrocytes produce both lactate and BHB, both of which can fuel neurons as energy substrates, via processes that are coupled with neuronal excitation [3]. Accumulating evidence supporting the actions of exogenous lactate and BHB as signal molecules that induce BDNF converge in this intracerebral metabolic compartment between neurons and astrocytes, where astrocyte-derived lactate and BHB support neuronal function in terms of both energy metabolism and synaptic plasticity [3].

### **2. Sources and roles of exercise-induced lactate and ketone bodies in the brain**

Physical activity is known to elevate lactate levels in the blood [13, 14]. Since physical activities are beneficial for the maintenance of both mental and physical health, an exploration of the mechanisms by which physical exercise improves neuronal function is an important target. Energetically, human brain function is solely dependent on the oxidative metabolism of glucose [4, 5]. Glucose is continuously supplied by the blood stream, since virtually no glucose storage exists in the brain. Besides the brain, only the testis is known to rely on glucose as an energy substrate [4, 5].

Glucose in the blood is taken up by glucose transporter 1 (Glut1) in the endothelium of brain microvessels [3–5, 17]. In addition to this glucose transporter, MCTs expressed in the brain microvessels allow lactate and ketone bodies *Lactate and Ketone Bodies Act as Energy Substrates as Well as Signal Molecules in the Brain DOI: http://dx.doi.org/10.5772/intechopen.97035*

(especially BHB) to cross the blood–brain barrier (BBB) [3–5, 17]. Neural cells (neurons and glia) are thus able to take up glucose, lactate, and BHB via glucose transporters or MCTs (**Figure 2**) [17]. Once lactate or BHB is transported into the brain cells, they enter the TCA cycle to act as energy substrates, similar to glucose (**Figure 3**). Although neither lactate nor BHB is an efficient energy substrate because of the slow transportation kinetics of MCTs, elevations in their blood concentrations allow them to act as energy sources supplied externally from the brain [3–5]. The concentrations of both lactate and BHB do, indeed, increase after physical exercise [28, 29]. The sources of the elevated lactate and BHB levels in the blood after physical activity are the skeletal muscles and liver, respectively [3–5]. Under starvation and insulin-resistance in diabetic patients, glucose availability in the peripheral tissue is limited, and BHB can fuel brain function in the place of glucose.

In addition to their roles as energy substrates, both lactate and BHB can improve brain function through synaptic plasticity. Ample evidence supports BDNF being a key molecule in the induction of neuronal plasticity [8, 9]. BDNF is a member of the neurotrophin family and is produced in neurons as well as glial cells [8, 9]. BDNF promotes neurite outgrowth, facilitates synaptic transmission, and regenerates the neuronal network. Recent evidence suggests that both lactate and BHB, which are produced outside the brain during physical exercise, act as signal molecules in the brain after crossing the BBB [13–16]. Lactate induces BDNF expression, and this action of lactate is dependent on the activation of Sirtuin1 deacetylase. Silent information regulator 1 (SIRT1) increases the levels of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and the secreted molecule fibronectin type III domain-containing protein 5 (FNDC5), which are known to mediate BDNF expression [13, 14]. In contrast, BHB induces BDNF expression by acting as a direct Class I histone deacetylase (HDAC) inhibitor. By inhibiting HDAC2 and HDAC3 and by preventing their recruitment to BDNF promoter I, BHB induces BDNF expression [15, 16].

#### **3. Lactate production and consumption in the brain**

In addition to skeletal muscles, numerous cells in the body generate lactate. Especially under a hypoxic/anoxic state, virtually all cell types generate lactate through glycolysis, since the further oxidation of lactate in the mitochondrial TCA cycle is inhibited because of oxygen unavailability [3–5]. Importantly, even under a sufficient supply of oxygen, lactate production can occur (aerobic glycolysis). Although brain function is dependent on the complete oxidation of glucose, cellular differences in the cell types should be noted. In fact, astroglia seem to be more glycolysis-dependent, compared with neurons (**Figure 5**) [3, 23]. Astroglia exhibit normal mitochondrial function and are capable of oxidizing glucose as well as lactate/pyruvate in mitochondria (**Figures 6**–**8**), albeit lactate/pyruvate does not seem to be an ideal substrate [3, 23].

Astroglial endfeet envelope brain microvessels as well as synapses (**Figure 9**) [30–32]. This anatomical location of astroglia seems to be suitable for the direct uptake of glucose from the microvessels [3]. Glucose is metabolized glycolytically in the astroglial cytosol, generating lactate/pyruvate (**Figure 9**). In contrast to neurons, however, ATP consumption by astroglia is much smaller than that by neurons, since astroglia do not generate action potentials. In fact, approximately one half of the total neuronal ATP consumption reflects Na+ ,K+ -ATPase activity, which restores and maintains the ionic gradient across the cell membrane to maintain the generation of action potentials [4, 5]. Astroglial Na+ ,K+ -ATPase also plays

#### **Figure 5.**

*Glucose consumption and lactate production measured directly in culture medium for rat astroglia and neurons (adapted from [23]).*

#### **Figure 6.**

*Competition assay 1: [14C]glucose oxidation is inhibited by lactate by approximately half in neurons but not in astroglia (adapted from [23]).*

a role in maintaining the ionic gradient, and this helps astroglia to take up glutamate released into the synaptic cleft (**Figure 9**) [3, 18, 33]. Glutamate is the most widely distributed excitatory transmitter, and primary motor neurons in the motor cortex release glutamate, which in turn activates secondary motor neurons in the spinal cord to induce muscle contraction. Whether glutamate re-uptake stimulates astroglial CMRglc and CMRoxy remains controversial [3, 18, 33–53]. In an in vitro culture model, at least, the application of glutamate increased glucose consumption (**Figure 10**) as well as lactate production (**Figure 11**), suggesting the activation of glycolysis in an CMRoxy-independent manner [3, 18, 33].

*Lactate and Ketone Bodies Act as Energy Substrates as Well as Signal Molecules in the Brain DOI: http://dx.doi.org/10.5772/intechopen.97035*

*Competition assay 2: [14C]lactate oxidation is somewhat inhibited by glucose in neurons but is markedly inhibited in astroglia (adapted from [23]).*

**Figure 8.**

*Competition assay 3: [1-14C]pyruvate oxidation is somewhat inhibited by glucose in neurons.*
