Diseases Due to Disturbances in Adipose Tissue

**75**

**Chapter 5**

**Abstract**

disruption.

**1. Introduction**

Adipose Tissue Inflammation and

Adipose tissue not only possesses an important role in the storage of excess nutrients but also acts as a critical immune and endocrine organ. Researchers and clinicians now consider adipose tissue to be an active endocrine organ that secretes various humoral factors called "adipokines," which imparts important systemic metabolic effects, from food intake to glucose tolerance. Along with its production of specialized adipokines, adipose tissue also secretes proinflammatory cytokines that likely contributes to the low-level systemic inflammation that has become a hallmark of various metabolic syndrome-associated chronic pathologies, such as obesity and cancer cachexia. These systemic effects may be mediated by communication networks arising from the multitude of resident adipose cells, including adipocytes, endothelial cells, neuronal cells, stem cells and other precursors, and a wide variety of immune cell populations that recent studies have demonstrated play a crucial role in the development of adipose inflammation and systemic metabolic abnormalities. In this chapter, we detail various molecular pathways linking excess adipose lipid storage to chronic inflammation and review the current knowledge as to what triggers obesity- and cachexia-associated inflammation in adipose tissue. Finally, we describe how the cross talk between adipose tissue inflammation and the non-adipocyte resident cells present in tissue is involved in this metabolic

**Keywords:** adipokines, remodeling, cross talk, cachexia, obesity

context of cancer cachexia and obesity will be further discussed.

In recent years, adipose tissue has rapidly emerged as a critical player in maintaining an organism's metabolic homeostasis through its canonical role in storing excess energy, as well as its emerging role in facilitating communication modalities critical to maintaining systemic metabolism. These diverse abilities possessed by adipose tissue directly results from its heterogeneous composition which allows for the integration and propagation of signals that influence whole-body homeostasis. To be effective in reacting to alterations within the organism, the adipose tissue must be dynamic and remodel itself in order to preserve the health of the organism. While remodeling allows for the maintenance of homeostasis, this mechanism may become compromised in certain metabolic diseases, such as cancer cachexia and obesity. Here, the influence of adipose heterogeneity on tissue remodeling in the

Metabolic Disorders

*and Miguel Luiz Batista Júnior*

*Felipe Henriques, Alexander H. Bedard* 

#### **Chapter 5**

## Adipose Tissue Inflammation and Metabolic Disorders

*Felipe Henriques, Alexander H. Bedard and Miguel Luiz Batista Júnior*

#### **Abstract**

Adipose tissue not only possesses an important role in the storage of excess nutrients but also acts as a critical immune and endocrine organ. Researchers and clinicians now consider adipose tissue to be an active endocrine organ that secretes various humoral factors called "adipokines," which imparts important systemic metabolic effects, from food intake to glucose tolerance. Along with its production of specialized adipokines, adipose tissue also secretes proinflammatory cytokines that likely contributes to the low-level systemic inflammation that has become a hallmark of various metabolic syndrome-associated chronic pathologies, such as obesity and cancer cachexia. These systemic effects may be mediated by communication networks arising from the multitude of resident adipose cells, including adipocytes, endothelial cells, neuronal cells, stem cells and other precursors, and a wide variety of immune cell populations that recent studies have demonstrated play a crucial role in the development of adipose inflammation and systemic metabolic abnormalities. In this chapter, we detail various molecular pathways linking excess adipose lipid storage to chronic inflammation and review the current knowledge as to what triggers obesity- and cachexia-associated inflammation in adipose tissue. Finally, we describe how the cross talk between adipose tissue inflammation and the non-adipocyte resident cells present in tissue is involved in this metabolic disruption.

**Keywords:** adipokines, remodeling, cross talk, cachexia, obesity

#### **1. Introduction**

In recent years, adipose tissue has rapidly emerged as a critical player in maintaining an organism's metabolic homeostasis through its canonical role in storing excess energy, as well as its emerging role in facilitating communication modalities critical to maintaining systemic metabolism. These diverse abilities possessed by adipose tissue directly results from its heterogeneous composition which allows for the integration and propagation of signals that influence whole-body homeostasis. To be effective in reacting to alterations within the organism, the adipose tissue must be dynamic and remodel itself in order to preserve the health of the organism. While remodeling allows for the maintenance of homeostasis, this mechanism may become compromised in certain metabolic diseases, such as cancer cachexia and obesity. Here, the influence of adipose heterogeneity on tissue remodeling in the context of cancer cachexia and obesity will be further discussed.

#### **2. The adipose tissue**

#### **2.1 Adipose heterogeneity**

Adipose tissue, or fat tissue, is classified in morphofunctional term into two distinct groups; (1) white adipose tissue (WAT), composed predominantly of unilocular adipocytes, with low mitochondrial density and low oxidative capacity, and (2) brown adipose tissue (BAT), predominantly composed of multilocular adipocytes, high mitochondrial density and oxidative capacity for the uptake and oxidation of fatty acids and glucose related to the maintenance and regulation of body temperature [1]. Other differences between the two types of adipose tissues are the depot localization, profile of secreted molecules, cell population, vascularization and also innervation [2–4]. While both of these adipose tissue groups contribute a significant role in maintaining systemic homeostasis, WAT is the primary site of metabolic dysregulation in many metabolic diseases [5, 6].

WAT is divided into two large depots, subcutaneous adipose tissue (scWAT) and visceral adipose tissue (vWAT). scWAT is present in the innermost layers of the skin (hypodermis), while vWAT is located in the internal organs [7]. In addition, it is well described, both in experimental and clinical research, that adipose tissue is a heterogeneous tissue, that presents different gene and protein expression profiles, as well as cellular composition depending on the location of the tissue [8, 9]. scWAT represents approximately 80% of the total fat mass in healthy individuals, while vWAT accounts for between 10 and 20% of the total body fat of lean men, and between 5 and 10% of total fat in women [10]. vWAT has been shown to be more metabolically responsive, and its accumulation has a higher correlation with obesity-related mortality [11].

The morphological composition of adipose tissue plays an important role in the homeostatic maintenance and tissue development. Adipose tissue is a special type of connective tissue composed of different cell types composed of approximately 50–70% adipocytes and 30–50% of stromal vascular fraction (SVF) cells, where the mesenchymal precursor cells, pre-adipocytes, fibroblasts, leukocytes, blood vessels, lymph nodes and nerves are present (**Figure 1**) [12–14]. Numerous studies have shown the cellular heterogeneity of adipose tissue is a critical component in the

#### **Figure 1.**

*Adipose tissue cellularity. The vast majority of the adipose tissue mass is composed of adipocytes (approximately 60%). There are many other cell types present in the adipose tissue. This specific portion of non-adipocytes is called the stromal vascular fraction (SVF) that is approximately 30% of the total cells in the tissue. In this portion are present mesenchymal precursor cells, pre-adipocytes, macrophages, others immune cells and endothelial cells.*

**77**

**Figure 2.**

*Adipose Tissue Inflammation and Metabolic Disorders DOI: http://dx.doi.org/10.5772/intechopen.88631*

**2.2 Adipose tissue as an endocrine organ**

places a greater emphasis on studies of adipose cellularity.

tissue's ability to act as a hub of metabolic equilibrium [8, 15, 16]. Discovering and understanding the role of each cell present in adipose tissue leads to a greater chance in the development of possible therapeutics targeting metabolic disorders, which

This endocrine role of adipose tissue is best characterized by leptin [17, 18]. In 1994, with the discovery of leptin, the perception of WAT evolved from simply an energy storage compartment, mechanical protector and thermal insulation, but also an endocrine organ due the identification of a multitude of adipocyte-secreted factors that can act on distal tissues to regulate systemic functions, such as immunological and inflammatory responses, regulation of appetite, vascular events, control of reproductive functions, and insulin sensitivity [17, 19]. Total deficiency or insensitivity to leptin causes hyperphagia, morbid obesity, diabetes, a variety of neuroendocrine abnormalities, and autonomic and immunologic dysfunction [20]. Studies show that adipose tissue-derived hormones, fatty acids, lipids and signaling molecules, act by exerting endocrine, autocrine and paracrine effects. These factors are part of the large family of proteins and small molecules released by adipose tissue, which collectively are called adipokines [17, 21]. This tremendous diversity of signaling molecules enables the adipose tissue to engage in a wide array of signaling modalities that allows for systemic regulation of an organism's physiology (**Figure 2**). In instances of whole-body metabolic dysregulation, such as cancer cachexia and obesity, alterations to adipose tissue composition may have drastic effects on adipokine production. These effects are of critical importance in understanding the manifestation of metabolic syndromes. One example of such a dysregulation in adipokine profile is the release of pro- and anti- inflammatory adipokines during pathophysiological processes. This adipokine dysregulation

*Adipose tissue as endocrine organ. Endocrine factors released by white fat may signal to distant issues, including the brain, muscle, liver, heart and pancreas that regulate glucose and fatty acid metabolism in peripheral tissues, energy homeostasis, inflammatory response, and blood pressure, among others. Imbalanced secretion of some of these adipokines is associated with metabolic disorders. These factors released by white adipose tissue may target itself in an autocrine and paracrine manner, and also activate distant tissues in an endocrine* 

*manner (e.g., brown adipose tissue). Abbreviations see appendices and nomenclature section.*

*Adipose Tissue - An Update*

**2. The adipose tissue**

**2.1 Adipose heterogeneity**

dysregulation in many metabolic diseases [5, 6].

correlation with obesity-related mortality [11].

Adipose tissue, or fat tissue, is classified in morphofunctional term into two distinct groups; (1) white adipose tissue (WAT), composed predominantly of unilocular adipocytes, with low mitochondrial density and low oxidative capacity, and (2) brown adipose tissue (BAT), predominantly composed of multilocular adipocytes, high mitochondrial density and oxidative capacity for the uptake and oxidation of fatty acids and glucose related to the maintenance and regulation of body temperature [1]. Other differences between the two types of adipose tissues are the depot localization, profile of secreted molecules, cell population, vascularization and also innervation [2–4]. While both of these adipose tissue groups contribute a significant role in maintaining systemic homeostasis, WAT is the primary site of metabolic

WAT is divided into two large depots, subcutaneous adipose tissue (scWAT) and visceral adipose tissue (vWAT). scWAT is present in the innermost layers of the skin (hypodermis), while vWAT is located in the internal organs [7]. In addition, it is well described, both in experimental and clinical research, that adipose tissue is a heterogeneous tissue, that presents different gene and protein expression profiles, as well as cellular composition depending on the location of the tissue [8, 9]. scWAT represents approximately 80% of the total fat mass in healthy individuals, while vWAT accounts for between 10 and 20% of the total body fat of lean men, and between 5 and 10% of total fat in women [10]. vWAT has been shown to be more metabolically responsive, and its accumulation has a higher

The morphological composition of adipose tissue plays an important role in the homeostatic maintenance and tissue development. Adipose tissue is a special type of connective tissue composed of different cell types composed of approximately 50–70% adipocytes and 30–50% of stromal vascular fraction (SVF) cells, where the mesenchymal precursor cells, pre-adipocytes, fibroblasts, leukocytes, blood vessels, lymph nodes and nerves are present (**Figure 1**) [12–14]. Numerous studies have shown the cellular heterogeneity of adipose tissue is a critical component in the

*Adipose tissue cellularity. The vast majority of the adipose tissue mass is composed of adipocytes* 

*(approximately 60%). There are many other cell types present in the adipose tissue. This specific portion of non-adipocytes is called the stromal vascular fraction (SVF) that is approximately 30% of the total cells in the tissue. In this portion are present mesenchymal precursor cells, pre-adipocytes, macrophages, others immune* 

**76**

**Figure 1.**

*cells and endothelial cells.*

tissue's ability to act as a hub of metabolic equilibrium [8, 15, 16]. Discovering and understanding the role of each cell present in adipose tissue leads to a greater chance in the development of possible therapeutics targeting metabolic disorders, which places a greater emphasis on studies of adipose cellularity.

#### **2.2 Adipose tissue as an endocrine organ**

This endocrine role of adipose tissue is best characterized by leptin [17, 18]. In 1994, with the discovery of leptin, the perception of WAT evolved from simply an energy storage compartment, mechanical protector and thermal insulation, but also an endocrine organ due the identification of a multitude of adipocyte-secreted factors that can act on distal tissues to regulate systemic functions, such as immunological and inflammatory responses, regulation of appetite, vascular events, control of reproductive functions, and insulin sensitivity [17, 19]. Total deficiency or insensitivity to leptin causes hyperphagia, morbid obesity, diabetes, a variety of neuroendocrine abnormalities, and autonomic and immunologic dysfunction [20].

Studies show that adipose tissue-derived hormones, fatty acids, lipids and signaling molecules, act by exerting endocrine, autocrine and paracrine effects. These factors are part of the large family of proteins and small molecules released by adipose tissue, which collectively are called adipokines [17, 21]. This tremendous diversity of signaling molecules enables the adipose tissue to engage in a wide array of signaling modalities that allows for systemic regulation of an organism's physiology (**Figure 2**). In instances of whole-body metabolic dysregulation, such as cancer cachexia and obesity, alterations to adipose tissue composition may have drastic effects on adipokine production. These effects are of critical importance in understanding the manifestation of metabolic syndromes. One example of such a dysregulation in adipokine profile is the release of pro- and anti- inflammatory adipokines during pathophysiological processes. This adipokine dysregulation

#### **Figure 2.**

*Adipose tissue as endocrine organ. Endocrine factors released by white fat may signal to distant issues, including the brain, muscle, liver, heart and pancreas that regulate glucose and fatty acid metabolism in peripheral tissues, energy homeostasis, inflammatory response, and blood pressure, among others. Imbalanced secretion of some of these adipokines is associated with metabolic disorders. These factors released by white adipose tissue may target itself in an autocrine and paracrine manner, and also activate distant tissues in an endocrine manner (e.g., brown adipose tissue). Abbreviations see appendices and nomenclature section.*

contributes significantly to the disruption of adipose tissue homeostasis in these diseases. Excessive secretion of potentially harmful adipokines (e.g., PAI-1, TNF-α and IL6) and hyposecretion of potentially beneficial adipokines, (e.g., adiponectin), may play an important role in the major mechanisms involved in during metabolic diseases. Thus, understanding the mechanism of various metabolic diseases calls for a deep understanding of the relationship between adipose tissue cellular composition and function.

#### **2.3 Adipose tissue remodeling**

Adipose tissue can respond rapidly and dynamically depending on the situation involved, thus fulfilling its major role in preserving whole-body energy homeostasis [22, 23]. Adipose tissue remodeling is a continuous process that is involved in some metabolic syndromes, such as reduction of vascular remodeling [24], overproduction of extracellular matrix [25], altered immune cell populations, and inflammatory responses are classic tissue response to such metabolic imbalances [26]. However, not all remodeling of adipose tissue is necessarily associated with pathological changes. A classic example is a concept of "metabolically healthy obesity" [27, 28], suggesting that some individuals may preserve systemic insulin sensitivity based on the "healthy" expansion of adipose tissue, avoiding the pathological consequences associated with obesity. Among the various consequences that can arise from adipose tissue remodeling is a state of local inflammation. This inflammatory state has been implicated in the progression of systemic dysregulation of metabolism in instances of "metabolically unhealthy obesity" [29]. Thus, comprehending the role of inflammation in the remodeling process of the adipose tissue is essential in understanding the main pathological alterations of this tissue.

#### *2.3.1 An overview of adipose tissue inflammation*

The adipose tissue plays host to a variety of immune cell populations that are intimately involved in the remodeling state of the tissue. Adipose tissue resident cells can secrete several proinflammatory cytokines that can orchestrate the inflammatory state of the tissue by influencing these immune cell populations within the tissue itself [21]. These inflammatory mediators have several metabolic and endocrine functions (immunity, metabolism, energy balance, among others), which is intimal related to the inflammatory process and immune system response [30, 31].

Inflammation in adipose tissue rose to prominence in the mid-1990s, shortly after obesity was recognized as an inflammatory disease in a study conducted with rats, which demonstrated greater expression of the gene encoding the proinflammatory cytokine TNF-α in adipose tissue, as well as a reduction in insulin sensitivity after exposure to a weight-gain diet [32]. In recent decades, data from human studies and transgenic animal models have strongly suggested correlative but also causative associations between the activation of proinflammatory pathways and insulin resistance [33, 34]. Particularly, chronic inflammation in adipose tissue appears to play an important role in the development of insulin resistance related to obesity and others metabolic diseases [33, 35]. The following potential mechanisms of adipose tissue inflammation and how this state is involved during the pathological process of cancer-associated cachexia and obesity are discussed.

#### *2.3.2 Adipose tissue inflammation during cancer cachexia*

Cancer cachexia syndrome is characterized by systemic inflammation, body weight loss, adipose tissue remodeling, and skeletal muscle wasting that cannot be

**79**

*Adipose Tissue Inflammation and Metabolic Disorders DOI: http://dx.doi.org/10.5772/intechopen.88631*

fully reversed by conventional nutritional support and leads to progressive functional impairment [36]. Interesting, that adipose tissue of cachectic cancer patients is a possible relevant systemic source of inflammatory molecules during the development of the disease [37]. Moreover, it is now well described in both experimental and clinical research that these changes are dependent on the location of adipose tissue (e.g., visceral versus subcutaneous), which is involved in differential depot response to the disease [8, 38]. WAT also secretes and responds to pro-inflammatory

mediators, as it also expresses several receptors for these secreted cytokines,

which are cells that characterize acute inflammation [46].

the presence of cachexia in humans [38].

In addition to animal models of cachexia, a study has recently demonstrated the presence of an exacerbated inflammatory profile in the WAT of humans with cancer cachexia [38]. In particular, an increase in CD68 positive cells, indicative of macrophages, and the clustering of the classic "crown-like structure" around the adipocyte were described. This morphological characteristic, although well-detailed in an obesity model, was described for the first time in cachexia. In the same study, an increase in CD3, a lymphocyte marker, and total collagen-positive cells in the WAT of these patients with cachexia was also detected. Taken together, the data indicate the presence of morphological alterations that suggest WAT remodeling in

However, despite the relevance of local inflammation, notably in WAT, the mechanisms that result in this process still require further detailing. Another important aspect is the characterization and understanding of the inflammatory process in this condition and its possible relation with the metabolic disorders, in order to answer if this process is secondary or the "trigger" for the development of the syndrome. Understanding the basic mechanisms of cancer cachexia that orchestrate WAT remodeling is relevant for the development of new pharmacological and nutritional therapies for anti-cachectic purposes. In this context, further demonstrating an intimate correlation between inflammation and the prognosis of cancer-associated cachexia, it was demonstrated that a genetic and pharmacological (atorvastatin) model of Toll-like receptor 4 (TLR4) inhibition, one of the primary inflammatory mediators, was able to attenuate classic symptoms of cachexia in an

chemokines, complement and growth factors [39]. These mediators act locally in an autocrine and/or paracrine manner, as well as distally in an endocrine fashion that can regulate appetite, modulate energy expenditure and affect a range of physiological processes, including insulin sensitivity and inflammatory responses [40]. Some interesting studies proposed that an imbalance between catabolic and anabolic processes in WAT is associated with the progression of cachexia. The proinflammatory cytokines interleukin 1-beta (IL-1β), interferon gamma (IFN-γ), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) appear responsible for the activation of WAT catabolism in experimental models [37, 41–44]. Additionally, studies have demonstrated a predominance of an inflammatory profile in the terminal phase of the cachexia syndrome, notably within vWAT [45]. The presence of an important macrophage infiltration in this depot in rats with cancer cachexia was verified, which has been shown to contribute to the secretion of inflammatory factors [45]. More recently, in the same model of cancer cachexia, Batista et al. [41] showed an increase of macrophages around the adipocytes that were are polarized to a proinflammatory state in the vWAT simultaneously with the activation of the inflammasome pathway in this specific depot [43]. This event was immediately preceded by an increase in neutrophil density within the depot, which usually occurs in the intermediate phases of the syndrome. Therefore, depending on the inflammatory phase, distinct cell types can be observed. In fact, in several inflammatory processes, chronic inflammation is characterized by the presence of mononuclear cells that is usually preceded by tissue infiltration of neutrophils,

#### *Adipose Tissue Inflammation and Metabolic Disorders DOI: http://dx.doi.org/10.5772/intechopen.88631*

*Adipose Tissue - An Update*

cellular composition and function.

**2.3 Adipose tissue remodeling**

contributes significantly to the disruption of adipose tissue homeostasis in these diseases. Excessive secretion of potentially harmful adipokines (e.g., PAI-1, TNF-α and IL6) and hyposecretion of potentially beneficial adipokines, (e.g., adiponectin), may play an important role in the major mechanisms involved in during metabolic diseases. Thus, understanding the mechanism of various metabolic diseases calls for a deep understanding of the relationship between adipose tissue

Adipose tissue can respond rapidly and dynamically depending on the situation involved, thus fulfilling its major role in preserving whole-body energy homeostasis [22, 23]. Adipose tissue remodeling is a continuous process that is involved in some metabolic syndromes, such as reduction of vascular remodeling [24], overproduction of extracellular matrix [25], altered immune cell populations, and inflammatory responses are classic tissue response to such metabolic imbalances [26]. However, not all remodeling of adipose tissue is necessarily associated with pathological changes. A classic example is a concept of "metabolically healthy obesity" [27, 28], suggesting that some individuals may preserve systemic insulin sensitivity based on the "healthy" expansion of adipose tissue, avoiding the pathological consequences associated with obesity. Among the various consequences that can arise from adipose tissue remodeling is a state of local inflammation. This inflammatory state has been implicated in the progression of systemic dysregulation of metabolism in instances of "metabolically unhealthy obesity" [29]. Thus, comprehending the role of inflammation in the remodeling process of the adipose tissue is essential

in understanding the main pathological alterations of this tissue.

cal process of cancer-associated cachexia and obesity are discussed.

Cancer cachexia syndrome is characterized by systemic inflammation, body weight loss, adipose tissue remodeling, and skeletal muscle wasting that cannot be

*2.3.2 Adipose tissue inflammation during cancer cachexia*

The adipose tissue plays host to a variety of immune cell populations that are intimately involved in the remodeling state of the tissue. Adipose tissue resident cells can secrete several proinflammatory cytokines that can orchestrate the inflammatory state of the tissue by influencing these immune cell populations within the tissue itself [21]. These inflammatory mediators have several metabolic and endocrine functions (immunity, metabolism, energy balance, among others), which is intimal related to the inflammatory process and immune system response [30, 31]. Inflammation in adipose tissue rose to prominence in the mid-1990s, shortly after obesity was recognized as an inflammatory disease in a study conducted with rats, which demonstrated greater expression of the gene encoding the proinflammatory cytokine TNF-α in adipose tissue, as well as a reduction in insulin sensitivity after exposure to a weight-gain diet [32]. In recent decades, data from human studies and transgenic animal models have strongly suggested correlative but also causative associations between the activation of proinflammatory pathways and insulin resistance [33, 34]. Particularly, chronic inflammation in adipose tissue appears to play an important role in the development of insulin resistance related to obesity and others metabolic diseases [33, 35]. The following potential mechanisms of adipose tissue inflammation and how this state is involved during the pathologi-

*2.3.1 An overview of adipose tissue inflammation*

**78**

fully reversed by conventional nutritional support and leads to progressive functional impairment [36]. Interesting, that adipose tissue of cachectic cancer patients is a possible relevant systemic source of inflammatory molecules during the development of the disease [37]. Moreover, it is now well described in both experimental and clinical research that these changes are dependent on the location of adipose tissue (e.g., visceral versus subcutaneous), which is involved in differential depot response to the disease [8, 38]. WAT also secretes and responds to pro-inflammatory mediators, as it also expresses several receptors for these secreted cytokines, chemokines, complement and growth factors [39]. These mediators act locally in an autocrine and/or paracrine manner, as well as distally in an endocrine fashion that can regulate appetite, modulate energy expenditure and affect a range of physiological processes, including insulin sensitivity and inflammatory responses [40].

Some interesting studies proposed that an imbalance between catabolic and anabolic processes in WAT is associated with the progression of cachexia. The proinflammatory cytokines interleukin 1-beta (IL-1β), interferon gamma (IFN-γ), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) appear responsible for the activation of WAT catabolism in experimental models [37, 41–44]. Additionally, studies have demonstrated a predominance of an inflammatory profile in the terminal phase of the cachexia syndrome, notably within vWAT [45]. The presence of an important macrophage infiltration in this depot in rats with cancer cachexia was verified, which has been shown to contribute to the secretion of inflammatory factors [45]. More recently, in the same model of cancer cachexia, Batista et al. [41] showed an increase of macrophages around the adipocytes that were are polarized to a proinflammatory state in the vWAT simultaneously with the activation of the inflammasome pathway in this specific depot [43]. This event was immediately preceded by an increase in neutrophil density within the depot, which usually occurs in the intermediate phases of the syndrome. Therefore, depending on the inflammatory phase, distinct cell types can be observed. In fact, in several inflammatory processes, chronic inflammation is characterized by the presence of mononuclear cells that is usually preceded by tissue infiltration of neutrophils, which are cells that characterize acute inflammation [46].

In addition to animal models of cachexia, a study has recently demonstrated the presence of an exacerbated inflammatory profile in the WAT of humans with cancer cachexia [38]. In particular, an increase in CD68 positive cells, indicative of macrophages, and the clustering of the classic "crown-like structure" around the adipocyte were described. This morphological characteristic, although well-detailed in an obesity model, was described for the first time in cachexia. In the same study, an increase in CD3, a lymphocyte marker, and total collagen-positive cells in the WAT of these patients with cachexia was also detected. Taken together, the data indicate the presence of morphological alterations that suggest WAT remodeling in the presence of cachexia in humans [38].

However, despite the relevance of local inflammation, notably in WAT, the mechanisms that result in this process still require further detailing. Another important aspect is the characterization and understanding of the inflammatory process in this condition and its possible relation with the metabolic disorders, in order to answer if this process is secondary or the "trigger" for the development of the syndrome. Understanding the basic mechanisms of cancer cachexia that orchestrate WAT remodeling is relevant for the development of new pharmacological and nutritional therapies for anti-cachectic purposes. In this context, further demonstrating an intimate correlation between inflammation and the prognosis of cancer-associated cachexia, it was demonstrated that a genetic and pharmacological (atorvastatin) model of Toll-like receptor 4 (TLR4) inhibition, one of the primary inflammatory mediators, was able to attenuate classic symptoms of cachexia in an

animal model [47]. This suggests that an important inflammatory pathway may be considered a promising target for therapeutic actions. It also further elucidates the mechanism by which cancer cachexia is manifested [47].

#### *2.3.3 Adipose tissue inflammation during obesity*

The incidence of overweight and obesity has increased substantially in the last decades worldwide is considered a worldwide epidemic, reducing the quality of life due to an increase in the physical and metabolic disability of individuals [48]. This occurs, at least partially, because of the obesity-induced insulin resistance and the fact that adipose tissue is not only an energy reservoir but also a secretory endocrine organ of cytokines, hormones, and proteins that affect the functionality of cells and tissues all over the body [49].

Recent studies have established association between obesity and systemic chronic low-grade inflammation [30, 50]. This association is characterized by, among other things, higher levels of circulating proinflammatory cytokines and fatty acids that can contribute to the development of the metabolic dysfunctions involved in the pathogenesis of its comorbidities [51].

It is well known that during this inflammation state in the adipose tissue, the tissue starts an intense remodeling in the adipose cell types present in the tissue. A major type of cell that plays an important role in the adipose tissue is the macrophages. Adipose tissue macrophage can be characterized in two different classes based on the expression of particular markers [52]. M1 macrophages or classically activated macrophages are characterized by *nitric oxide* synthase (*iNOS*) and CD11c surface expression, and expression of pro-inflammatory cytokines [53]. On the other hand, M2 macrophages or alternatively activated macrophages, are characterized by *Arginase* 1 (Arg1) and CD206 surface expression, and secrete anti-inflammatory cytokines predominates [53].

#### **Figure 3.**

*Features in adipose tissue inflammation. Healthy adipose tissue displays high insulin sensitivity and is characterized by an anti-inflammatory state marked by elevated levels of adipocyte progenitor cells and M2 macrophages, sufficient vasculature to support tissue expansion and adipocyte hyperplasia. In an obese state, the adipose tissue contains hypertrophic adipocytes and a state of chronic inflammation exists within the tissue. A large increase in the populations of M1 proinflammatory macrophages, along with several other inflammatory leukocytes, begins to infiltrate the inflamed tissue. In addition, it is possible to observe a reduction in the vascularization of this unhealthy fat, resulting in a hypoxic state. Chronic inflammation results in the development of fibrotic structures in the form of increased extracellular components, such as collagen. Such events contribute to the development of insulin resistance.*

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*Adipose Tissue Inflammation and Metabolic Disorders DOI: http://dx.doi.org/10.5772/intechopen.88631*

tion is necessary to sustain the adipose tissue homeostasis.

tissue remodeling [24, 26, 56] (**Figure 3**).

**3. Concluding remarks**

**Acknowledgements**

**Conflict of interest**

A proposed model was defined as "phenotypic switching" that means an enhanced adipose tissue macrophage infiltration aggravates the environment of obesity-related inflammation [54]. This model emphasized that obesity starts to induced a polarization in these macrophage cells present in the tissue, that now the ratio M1/M2 macrophage are dysregulated and the M1 macrophage population are predominate in the adipose tissue [54]. Interesting that some studies showed that M1 macrophage population demonstrates a positive correlation with insulin resistance and an increase in proinflammatory responses [55]. Therefore, these studies suggest a sophisticated balance in relation to the diversity of macrophages popula-

In addition to this deregulation in macrophages infiltration, other major changes

also appear in the inflamed adipose tissue during obesity. Modifications in the composition of the extracellular matrix, decreased in the vascularization and alterations in the composition of immune cells in tissue are classic features of this adipose

In summary, certain metabolic disease states, such as cancer cachexia and obesity, may alter the heterogeneous composition of adipose tissue, resulting in a remodeled tissue that is unable to properly respond to the systemic needs of the organism. We know that the adipose heterogeneity cells present in the tissue are the extremely importance in to regulate the homeostasis, and in the time that adipose tissue is affected to some metabolic syndrome this cross talk is deregulated and the homeostasis is compromised. After the adipose tissue is committed by a metabolic syndrome, the tissue starts to react in several ways. Several studies using cachexia and obesity experimental models have consistently indicated that a classic response to this imbalance, showed an intense adipose tissue remodeling in which the tissue begins to present numerous alterations in the morphology and also genetic alterations where its function ends up being extremely compromised. Finally, a deeper understanding of the initial stimulus and also who are the main types of cells involved in adipose tissue remodeling is essential for understanding the basic mechanisms in which adipose tissue performs. Once we have managed to obtain the answers to these important issues, we will be able to advance and have the chance to

achieve some possible therapeutic target to these severe metabolic diseases.

Diabetes Association (ADA)—Grant #1-19-PMF-035.

The authors declare no conflicts of interest.

BDNF brain-derived neurotrophic factor

**Appendices and nomenclature**

BAT brown adipose tissue

The authors gratefully acknowledge the commitment and support by American

*Adipose Tissue - An Update*

tissues all over the body [49].

animal model [47]. This suggests that an important inflammatory pathway may be considered a promising target for therapeutic actions. It also further elucidates the

The incidence of overweight and obesity has increased substantially in the last decades worldwide is considered a worldwide epidemic, reducing the quality of life due to an increase in the physical and metabolic disability of individuals [48]. This occurs, at least partially, because of the obesity-induced insulin resistance and the fact that adipose tissue is not only an energy reservoir but also a secretory endocrine organ of cytokines, hormones, and proteins that affect the functionality of cells and

Recent studies have established association between obesity and systemic chronic low-grade inflammation [30, 50]. This association is characterized by, among other things, higher levels of circulating proinflammatory cytokines and fatty acids that can contribute to the development of the metabolic dysfunctions

surface expression, and secrete anti-inflammatory cytokines predominates [53].

*Features in adipose tissue inflammation. Healthy adipose tissue displays high insulin sensitivity and is characterized by an anti-inflammatory state marked by elevated levels of adipocyte progenitor cells and M2 macrophages, sufficient vasculature to support tissue expansion and adipocyte hyperplasia. In an obese state, the adipose tissue contains hypertrophic adipocytes and a state of chronic inflammation exists within the tissue. A large increase in the populations of M1 proinflammatory macrophages, along with several other inflammatory leukocytes, begins to infiltrate the inflamed tissue. In addition, it is possible to observe a reduction in the vascularization of this unhealthy fat, resulting in a hypoxic state. Chronic inflammation results in the development of fibrotic structures in the form of increased extracellular components, such as collagen.* 

*Such events contribute to the development of insulin resistance.*

It is well known that during this inflammation state in the adipose tissue, the tissue starts an intense remodeling in the adipose cell types present in the tissue. A major type of cell that plays an important role in the adipose tissue is the macrophages. Adipose tissue macrophage can be characterized in two different classes based on the expression of particular markers [52]. M1 macrophages or classically activated macrophages are characterized by *nitric oxide* synthase (*iNOS*) and CD11c surface expression, and expression of pro-inflammatory cytokines [53]. On the other hand, M2 macrophages or alternatively activated macrophages, are characterized by *Arginase* 1 (Arg1) and CD206

mechanism by which cancer cachexia is manifested [47].

involved in the pathogenesis of its comorbidities [51].

*2.3.3 Adipose tissue inflammation during obesity*

**80**

**Figure 3.**

A proposed model was defined as "phenotypic switching" that means an enhanced adipose tissue macrophage infiltration aggravates the environment of obesity-related inflammation [54]. This model emphasized that obesity starts to induced a polarization in these macrophage cells present in the tissue, that now the ratio M1/M2 macrophage are dysregulated and the M1 macrophage population are predominate in the adipose tissue [54]. Interesting that some studies showed that M1 macrophage population demonstrates a positive correlation with insulin resistance and an increase in proinflammatory responses [55]. Therefore, these studies suggest a sophisticated balance in relation to the diversity of macrophages population is necessary to sustain the adipose tissue homeostasis.

In addition to this deregulation in macrophages infiltration, other major changes also appear in the inflamed adipose tissue during obesity. Modifications in the composition of the extracellular matrix, decreased in the vascularization and alterations in the composition of immune cells in tissue are classic features of this adipose tissue remodeling [24, 26, 56] (**Figure 3**).

### **3. Concluding remarks**

In summary, certain metabolic disease states, such as cancer cachexia and obesity, may alter the heterogeneous composition of adipose tissue, resulting in a remodeled tissue that is unable to properly respond to the systemic needs of the organism. We know that the adipose heterogeneity cells present in the tissue are the extremely importance in to regulate the homeostasis, and in the time that adipose tissue is affected to some metabolic syndrome this cross talk is deregulated and the homeostasis is compromised. After the adipose tissue is committed by a metabolic syndrome, the tissue starts to react in several ways. Several studies using cachexia and obesity experimental models have consistently indicated that a classic response to this imbalance, showed an intense adipose tissue remodeling in which the tissue begins to present numerous alterations in the morphology and also genetic alterations where its function ends up being extremely compromised. Finally, a deeper understanding of the initial stimulus and also who are the main types of cells involved in adipose tissue remodeling is essential for understanding the basic mechanisms in which adipose tissue performs. Once we have managed to obtain the answers to these important issues, we will be able to advance and have the chance to achieve some possible therapeutic target to these severe metabolic diseases.

#### **Acknowledgements**

The authors gratefully acknowledge the commitment and support by American Diabetes Association (ADA)—Grant #1-19-PMF-035.

#### **Conflict of interest**

The authors declare no conflicts of interest.

#### **Appendices and nomenclature**



### **Author details**

Felipe Henriques1 \*, Alexander H. Bedard1 and Miguel Luiz Batista Júnior2

1 Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA

2 Laboratory of Adipose Tissue Biology, Integrated Group of Biotechnology, University of Mogi das Cruzes, Mogi das Cruzes, SP, Brazil

\*Address all correspondence to: felipe.henriques@umassmed.edu

© 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.

**83**

*Adipose Tissue Inflammation and Metabolic Disorders DOI: http://dx.doi.org/10.5772/intechopen.88631*

> [11] Lafontan M, Girard J. Impact of visceral adipose tissue on liver metabolism. Part I: Heterogeneity of adipose tissue and functional properties of visceral adipose tissue. Diabetes & Metabolism. 2008;**34**(4 Pt 1):317-327

[12] Gesta S, Tseng YH, Kahn CR. Developmental origin of fat: Tracking obesity to its source. Cell.

[13] Hausman GJ, Barb CR, Dean RG.

Gene expression profiling in developing pig adipose tissue: Nonsecreted regulatory proteins. Animal.

[14] Guilherme A et al. Molecular pathways linking adipose innervation to insulin action in obesity and diabetes mellitus. Nature Reviews. Endocrinology. 2019;**15**(4):207-225

[15] Lee YH et al. Metabolic

2018;**221**:jeb162958

2004;**89**(6):2548-2556

1994;**372**(6505):425-432

1078-1081

[18] Zhang Y et al. Positional cloning of the mouse obese gene and its human homologue. Nature.

[19] Trayhurn P, Wood IS. Signalling role of adipose tissue: Adipokines and inflammation in obesity. Biochemical Society Transactions. 2005;**33**(Pt 5):

heterogeneity of activated beige/brite adipocytes in inguinal adipose tissue. Scientific Reports. 2017;**7**:39794

[16] Schoettl T, Fischer IP, Ussar S. Heterogeneity of adipose tissue in development and metabolic function. The Journal of Experimental Biology.

[17] Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. The Journal of Clinical Endocrinology and Metabolism.

2007;**131**(2):242-256

2011;**5**(7):1071-1081

**References**

[1] Cinti S. The adipose organ:

tissues. The Proceedings of the Nutrition Society. 2001;**60**(3):319-328

Morphological perspectives of adipose

[2] Bartelt A et al. Brown adipose tissue activity controls triglyceride clearance. Nature Medicine. 2011;**17**(2):200-205

[3] Rosell M et al. Brown and white adipose tissues: Intrinsic differences in gene expression and response to cold exposure in mice. American Journal of Physiology. Endocrinology and Metabolism. 2014;**306**(8):E945-E964

[4] Vidal-Puig A. Adipose tissue expandability, lipotoxicity and the metabolic syndrome. Endocrinología y Nutrición. 2013;**60**(Suppl 1):39-43

[5] Ghaben AL, Scherer PE.

2019;**20**(4):242-258

2010;**11**(1):11-18

2012;**215**(3):363-373

2012;**5**(5):588-594

2010;**31**(10):384-390

Adipogenesis and metabolic health. Nature Reviews. Molecular Cell Biology.

[6] Wang L et al. PAI-1 exacerbates white adipose tissue dysfunction and metabolic dysregulation in high fat diet-induced obesity. Frontiers in Pharmacology. 2018;**9**:1087

[7] Ibrahim MM. Subcutaneous and visceral adipose tissue: Structural and functional differences. Obesity Reviews.

[8] Batista ML Jr et al. Heterogeneous time-dependent response of adipose tissue during the development of cancer cachexia. The Journal of Endocrinology.

[9] Cinti S. The adipose organ at a glance. Disease Models & Mechanisms.

immunity and adipose tissue biology. Trends in Immunology.

[10] Kaminski DA, Randall TD. Adaptive

*Adipose Tissue Inflammation and Metabolic Disorders DOI: http://dx.doi.org/10.5772/intechopen.88631*

#### **References**

*Adipose Tissue - An Update*

ECM extracellular matrix

NGF nerve growth factor NRG4 neuregulin 4

TLR4 Toll-like receptor 4 TNFα tumor necrosis factor α UCP1 uncoupling protein 1 vWAT visceral adipose tissue

WAT white adipose tissue

IL6 interleukin 6 IL1β interleukin 1β IL10 interleukin 10 IL33 interleukin 33

GDF15 growth differentiation factor 15 IGF-1 insulin-like growth factor 1

NEGR1 neuronal growth regulator 1

PAI-1 plasminogen activator inhibitor-1 scWAT subcutaneous adipose tissue SVF stromal vascular fraction TGF-β transforming growth factor β

VEGF vascular endothelial growth factor

**82**

**Author details**

Felipe Henriques1

Worcester, MA, USA

\*, Alexander H. Bedard1

University of Mogi das Cruzes, Mogi das Cruzes, SP, Brazil

provided the original work is properly cited.

\*Address all correspondence to: felipe.henriques@umassmed.edu

1 Program in Molecular Medicine, University of Massachusetts Medical School,

2 Laboratory of Adipose Tissue Biology, Integrated Group of Biotechnology,

© 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,

and Miguel Luiz Batista Júnior2

[1] Cinti S. The adipose organ: Morphological perspectives of adipose tissues. The Proceedings of the Nutrition Society. 2001;**60**(3):319-328

[2] Bartelt A et al. Brown adipose tissue activity controls triglyceride clearance. Nature Medicine. 2011;**17**(2):200-205

[3] Rosell M et al. Brown and white adipose tissues: Intrinsic differences in gene expression and response to cold exposure in mice. American Journal of Physiology. Endocrinology and Metabolism. 2014;**306**(8):E945-E964

[4] Vidal-Puig A. Adipose tissue expandability, lipotoxicity and the metabolic syndrome. Endocrinología y Nutrición. 2013;**60**(Suppl 1):39-43

[5] Ghaben AL, Scherer PE. Adipogenesis and metabolic health. Nature Reviews. Molecular Cell Biology. 2019;**20**(4):242-258

[6] Wang L et al. PAI-1 exacerbates white adipose tissue dysfunction and metabolic dysregulation in high fat diet-induced obesity. Frontiers in Pharmacology. 2018;**9**:1087

[7] Ibrahim MM. Subcutaneous and visceral adipose tissue: Structural and functional differences. Obesity Reviews. 2010;**11**(1):11-18

[8] Batista ML Jr et al. Heterogeneous time-dependent response of adipose tissue during the development of cancer cachexia. The Journal of Endocrinology. 2012;**215**(3):363-373

[9] Cinti S. The adipose organ at a glance. Disease Models & Mechanisms. 2012;**5**(5):588-594

[10] Kaminski DA, Randall TD. Adaptive immunity and adipose tissue biology. Trends in Immunology. 2010;**31**(10):384-390

[11] Lafontan M, Girard J. Impact of visceral adipose tissue on liver metabolism. Part I: Heterogeneity of adipose tissue and functional properties of visceral adipose tissue. Diabetes & Metabolism. 2008;**34**(4 Pt 1):317-327

[12] Gesta S, Tseng YH, Kahn CR. Developmental origin of fat: Tracking obesity to its source. Cell. 2007;**131**(2):242-256

[13] Hausman GJ, Barb CR, Dean RG. Gene expression profiling in developing pig adipose tissue: Nonsecreted regulatory proteins. Animal. 2011;**5**(7):1071-1081

[14] Guilherme A et al. Molecular pathways linking adipose innervation to insulin action in obesity and diabetes mellitus. Nature Reviews. Endocrinology. 2019;**15**(4):207-225

[15] Lee YH et al. Metabolic heterogeneity of activated beige/brite adipocytes in inguinal adipose tissue. Scientific Reports. 2017;**7**:39794

[16] Schoettl T, Fischer IP, Ussar S. Heterogeneity of adipose tissue in development and metabolic function. The Journal of Experimental Biology. 2018;**221**:jeb162958

[17] Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. The Journal of Clinical Endocrinology and Metabolism. 2004;**89**(6):2548-2556

[18] Zhang Y et al. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;**372**(6505):425-432

[19] Trayhurn P, Wood IS. Signalling role of adipose tissue: Adipokines and inflammation in obesity. Biochemical Society Transactions. 2005;**33**(Pt 5): 1078-1081

[20] Harris RB. Direct and indirect effects of leptin on adipocyte metabolism. Biochimica et Biophysica Acta. 2014;**1842**(3):414-423

[21] Fantuzzi G. Adipose tissue, adipokines, and inflammation. The Journal of Allergy and Clinical Immunology. 2005;**115**(5):911-919. quiz 920

[22] Trujillo ME, Scherer PE. Adipose tissue-derived factors: Impact on health and disease. Endocrine Reviews. 2006;**27**(7):762-778

[23] Wernstedt Asterholm I et al. Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling. Cell Metabolism. 2014;**20**(1):103-118

[24] Sun K, Kusminski CM, Scherer PE. Adipose tissue remodeling and obesity. The Journal of Clinical Investigation. 2011;**121**(6):2094-2101

[25] Lin, Chun TH, Kang L. Adipose extracellular matrix remodelling in obesity and insulin resistance. Biochemical Pharmacology. 2016;**119**:8-16

[26] Choe SS et al. Adipose tissue remodeling: Its role in energy metabolism and metabolic disorders. Frontiers in Endocrinology. 2016;**7**:30

[27] Jung CH, Lee WJ, Song KH. Metabolically healthy obesity: A friend or foe? The Korean Journal of Internal Medicine. 2017;**32**(4):611-621

[28] Mongraw-Chaffin M et al. Metabolically healthy obesity, transition to metabolic syndrome, and cardiovascular risk. Journal of the American College of Cardiology. 2018;**71**(17):1857-1865

[29] Iacobini C et al. Metabolically healthy versus metabolically unhealthy obesity. Metabolism. 2019;**92**:51-60

[30] Monteiro R, Azevedo I. Chronic inflammation in obesity and the metabolic syndrome. Mediators of Inflammation. 2010;**2010**(289645):1-10

[31] Sharma P. Inflammation and the metabolic syndrome. Indian Journal of Clinical Biochemistry. 2011;**26**(4):317-318

[32] Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: Direct role in obesity-linked insulin resistance. Science. 1993;**259**(5091):87-91

[33] de Luca C, Olefsky JM. Inflammation and insulin resistance. FEBS Letters. 2008;**582**(1):97-105

[34] Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. The Journal of Clinical Investigation. 2006;**116**(7):1793-1801

[35] Czech MP. Insulin action and resistance in obesity and type 2 diabetes. Nature Medicine. 2017;**23**(7):804-814

[36] Fearon K, Arends J, Baracos V. Understanding the mechanisms and treatment options in cancer cachexia. Nature Reviews. Clinical Oncology. 2013;**10**(2):90-99

[37] Batista ML Jr et al. Adipose tissuederived factors as potential biomarkers in cachectic cancer patients. Cytokine. 2013;**61**(2):532-539

[38] Batista ML Jr et al. Cachexiaassociated adipose tissue morphological rearrangement in gastrointestinal cancer patients. Journal of Cachexia, Sarcopenia and Muscle. 2016;**7**(1):37-47

[39] Arner P. The adipocyte in insulin resistance: Key molecules and the impact of the thiazolidinediones. Trends in Endocrinology and Metabolism. 2003;**14**(3):137-145

**85**

*Adipose Tissue Inflammation and Metabolic Disorders DOI: http://dx.doi.org/10.5772/intechopen.88631*

[49] Coelho M, Oliveira T,

2014;**3**(4):422-431

2018;**162**(2):79-82

Fernandes R. Biochemistry of adipose tissue: An endocrine organ. Archives of Medical Science. 2013;**9**(2):191-200

[50] Pereira SS, Alvarez-Leite JI. Lowgrade inflammation, obesity, and diabetes. Current Obesity Reports.

[51] Rehman K, Akash MS. Mechanisms

of inflammatory responses and development of insulin resistance: How are they interlinked? Journal of Biomedical Science. 2016;**23**(1):87

[52] Chylikova J et al. M1/M2 macrophage polarization in human obese adipose tissue. Biomedical Papers of the Medical Faculty of the University Palacky, Olomouc, Czech Republic.

[53] Weisser SB et al. Generation and characterization of murine alternatively activated macrophages. Methods in Molecular Biology. 2013;**946**:225-239

[54] Lumeng CN et al. Phenotypic switching of adipose tissue

2008;**57**(12):3239-3246

2007;**56**(12):2910-2918

macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes.

[55] Castoldi A et al. The macrophage switch in obesity development. Frontiers in Immunology. 2015;**6**:637

[56] Strissel KJ et al. Adipocyte death, adipose tissue remodeling, and obesity complications. Diabetes.

[40] Mantovani A et al. Cancerrelated inflammation. Nature. 2008;**454**(7203):436-444

[42] Beluzi M et al. Pioglitazone treatment increases survival and prevents body weight loss in tumorbearing animals: Possible anti-cachectic effect. PLoS One. 2015;**10**(3):e0122660

2016;**7**(2):193-203

2018;**4**(7):e00708

[41] Batista ML Jr et al. Adipose tissue inflammation and cancer cachexia: Possible role of nuclear transcription factors. Cytokine. 2012;**57**(1):9-16

[43] Neves RX et al. White adipose tissue cells and the progression of cachexia: Inflammatory pathways. Journal of Cachexia, Sarcopenia and Muscle.

[44] Lopes MA et al. LLC tumor cellsderivated factors reduces adipogenesis

in co-culture system. Heliyon.

[45] Machado AP, Costa Rosa LF, Seelaender MC. Adipose tissue in Walker 256 tumour-induced cachexia: Possible association between decreased leptin concentration and mononuclear cell infiltration. Cell and Tissue Research. 2004;**318**(3):503-514

[46] Schymeinsky J, Mocsai A, Walzog B. Neutrophil activation via beta2 integrins (CD11/CD18): Molecular mechanisms and clinical implications.

Thrombosis and Haemostasis.

[47] Henriques F et al. Toll-like receptor-4 disruption suppresses adipose tissue remodeling and increases survival in cancer cachexia syndrome. Scientific Reports. 2018;**8**(1):18024

[48] Ng M et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: A systematic analysis for the global burden of disease study. Lancet.

2013;**2014, 384**(9945):766-781

2007;**98**(2):262-273

*Adipose Tissue Inflammation and Metabolic Disorders DOI: http://dx.doi.org/10.5772/intechopen.88631*

[40] Mantovani A et al. Cancerrelated inflammation. Nature. 2008;**454**(7203):436-444

*Adipose Tissue - An Update*

[20] Harris RB. Direct and indirect effects of leptin on adipocyte

Acta. 2014;**1842**(3):414-423

quiz 920

2006;**27**(7):762-778

2014;**20**(1):103-118

2011;**121**(6):2094-2101

2016;**119**:8-16

[21] Fantuzzi G. Adipose tissue, adipokines, and inflammation. The Journal of Allergy and Clinical Immunology. 2005;**115**(5):911-919.

metabolism. Biochimica et Biophysica

[30] Monteiro R, Azevedo I. Chronic inflammation in obesity and the metabolic syndrome. Mediators of Inflammation. 2010;**2010**(289645):1-10

[31] Sharma P. Inflammation and the metabolic syndrome. Indian Journal of Clinical Biochemistry.

[32] Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: Direct role in obesity-linked insulin resistance.

Science. 1993;**259**(5091):87-91

Inflammation and insulin resistance. FEBS Letters. 2008;**582**(1):97-105

[34] Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. The Journal of Clinical Investigation.

[35] Czech MP. Insulin action and

[36] Fearon K, Arends J, Baracos V. Understanding the mechanisms and treatment options in cancer cachexia. Nature Reviews. Clinical Oncology.

[37] Batista ML Jr et al. Adipose tissuederived factors as potential biomarkers in cachectic cancer patients. Cytokine.

[38] Batista ML Jr et al. Cachexia-

morphological rearrangement in gastrointestinal cancer patients. Journal of Cachexia, Sarcopenia and

[39] Arner P. The adipocyte in insulin resistance: Key molecules and the impact of the thiazolidinediones. Trends in Endocrinology and Metabolism.

associated adipose tissue

Muscle. 2016;**7**(1):37-47

2003;**14**(3):137-145

resistance in obesity and type 2 diabetes. Nature Medicine. 2017;**23**(7):804-814

[33] de Luca C, Olefsky JM.

2006;**116**(7):1793-1801

2013;**10**(2):90-99

2013;**61**(2):532-539

2011;**26**(4):317-318

[22] Trujillo ME, Scherer PE. Adipose tissue-derived factors: Impact on health and disease. Endocrine Reviews.

[23] Wernstedt Asterholm I et al. Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling. Cell Metabolism.

[24] Sun K, Kusminski CM, Scherer PE. Adipose tissue remodeling and obesity. The Journal of Clinical Investigation.

[25] Lin, Chun TH, Kang L. Adipose extracellular matrix remodelling in obesity and insulin resistance. Biochemical Pharmacology.

[26] Choe SS et al. Adipose tissue remodeling: Its role in energy

[27] Jung CH, Lee WJ, Song KH. Metabolically healthy obesity: A friend or foe? The Korean Journal of Internal

Medicine. 2017;**32**(4):611-621

[28] Mongraw-Chaffin M et al. Metabolically healthy obesity, transition to metabolic syndrome, and cardiovascular risk. Journal of the American College of Cardiology.

[29] Iacobini C et al. Metabolically healthy versus metabolically unhealthy obesity. Metabolism. 2019;**92**:51-60

2018;**71**(17):1857-1865

metabolism and metabolic disorders. Frontiers in Endocrinology. 2016;**7**:30

**84**

[41] Batista ML Jr et al. Adipose tissue inflammation and cancer cachexia: Possible role of nuclear transcription factors. Cytokine. 2012;**57**(1):9-16

[42] Beluzi M et al. Pioglitazone treatment increases survival and prevents body weight loss in tumorbearing animals: Possible anti-cachectic effect. PLoS One. 2015;**10**(3):e0122660

[43] Neves RX et al. White adipose tissue cells and the progression of cachexia: Inflammatory pathways. Journal of Cachexia, Sarcopenia and Muscle. 2016;**7**(2):193-203

[44] Lopes MA et al. LLC tumor cellsderivated factors reduces adipogenesis in co-culture system. Heliyon. 2018;**4**(7):e00708

[45] Machado AP, Costa Rosa LF, Seelaender MC. Adipose tissue in Walker 256 tumour-induced cachexia: Possible association between decreased leptin concentration and mononuclear cell infiltration. Cell and Tissue Research. 2004;**318**(3):503-514

[46] Schymeinsky J, Mocsai A, Walzog B. Neutrophil activation via beta2 integrins (CD11/CD18): Molecular mechanisms and clinical implications. Thrombosis and Haemostasis. 2007;**98**(2):262-273

[47] Henriques F et al. Toll-like receptor-4 disruption suppresses adipose tissue remodeling and increases survival in cancer cachexia syndrome. Scientific Reports. 2018;**8**(1):18024

[48] Ng M et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: A systematic analysis for the global burden of disease study. Lancet. 2013;**2014, 384**(9945):766-781

[49] Coelho M, Oliveira T, Fernandes R. Biochemistry of adipose tissue: An endocrine organ. Archives of Medical Science. 2013;**9**(2):191-200

[50] Pereira SS, Alvarez-Leite JI. Lowgrade inflammation, obesity, and diabetes. Current Obesity Reports. 2014;**3**(4):422-431

[51] Rehman K, Akash MS. Mechanisms of inflammatory responses and development of insulin resistance: How are they interlinked? Journal of Biomedical Science. 2016;**23**(1):87

[52] Chylikova J et al. M1/M2 macrophage polarization in human obese adipose tissue. Biomedical Papers of the Medical Faculty of the University Palacky, Olomouc, Czech Republic. 2018;**162**(2):79-82

[53] Weisser SB et al. Generation and characterization of murine alternatively activated macrophages. Methods in Molecular Biology. 2013;**946**:225-239

[54] Lumeng CN et al. Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes. 2008;**57**(12):3239-3246

[55] Castoldi A et al. The macrophage switch in obesity development. Frontiers in Immunology. 2015;**6**:637

[56] Strissel KJ et al. Adipocyte death, adipose tissue remodeling, and obesity complications. Diabetes. 2007;**56**(12):2910-2918

**87**

**Chapter 6**

**Abstract**

treatments.

**1. Introduction**

issues (**Table 1**) [1, 2].

lipedema [5, 6].

Tissue Disorder

Lipedema: A Painful Adipose

*Sara Al-Ghadban, Karen L. Herbst and Bruce A. Bunnell*

Lipedema is a painful fat disease of loose connective tissue usually misdiagnosed

as lifestyle-induced obesity that affects ~10% of women of European descent as well as other populations. Lipedema is characterized by symmetric enlargement of the buttocks, hips, and legs due to increased loose connective tissue; arms are also affected in 80% of patients. Lipedema loose connective tissue is characterized by hypertrophic adipocytes, inflammatory cells, and dilated leaky blood and lymphatic vessels. Altered fluid flux through the tissue causes accumulation of fluid, protein, and other constituents in the interstitium resulting in recruitment of inflammatory cells, which in turn stimulates fibrosis and results in difficulty in weight loss. Inflammation and excess interstitial substance may also activate nerve fibers instigating the painful lipedema fat tissue. More research is needed to characterize lipedema loose connective tissue structure in depth, as well as the form and function of blood and lymphatic vessels. Understanding the pathophysiology of the disease will allow healthcare providers to diagnose the disease and develop

**Keywords:** lipedema, symptoms, diagnosis, treatment, blood vessels, lymphatics

Loose connective tissue disorders include lipedema, Dercum's disease (DD), familial multiple lipomatosis (FML) and multiple symmetric lipomatosis (MSL). All these disorders share many similarities with lipedema including painful lipomas, obesity, fibrosis, a risk of developing lymphedema and difficulty in losing the abnormal fat through diet and exercise. There are clinical characteristics specific for lipedema, including the onset of the disease, fat location and associated health

Lipedema is often misdiagnosed as lifestyle-induced obesity that affects ~10% of women of European descent as well as other populations [3, 4]. Although both disorders are considered inflammatory diseases due to the presence of increased macrophages and hypertrophic adipocytes, there are significant differences between the two disorders. Among these is the location of the fat, primarily abdominal or spread widely over the body in obesity compared to the symmetric distribution in the lower extremities in lipedema, the texture of the skin (thin and soft in lipedema and thicker in obesity), easy bruising and pain upon the introduction of pressure in

#### **Chapter 6**

## Lipedema: A Painful Adipose Tissue Disorder

*Sara Al-Ghadban, Karen L. Herbst and Bruce A. Bunnell*

#### **Abstract**

Lipedema is a painful fat disease of loose connective tissue usually misdiagnosed as lifestyle-induced obesity that affects ~10% of women of European descent as well as other populations. Lipedema is characterized by symmetric enlargement of the buttocks, hips, and legs due to increased loose connective tissue; arms are also affected in 80% of patients. Lipedema loose connective tissue is characterized by hypertrophic adipocytes, inflammatory cells, and dilated leaky blood and lymphatic vessels. Altered fluid flux through the tissue causes accumulation of fluid, protein, and other constituents in the interstitium resulting in recruitment of inflammatory cells, which in turn stimulates fibrosis and results in difficulty in weight loss. Inflammation and excess interstitial substance may also activate nerve fibers instigating the painful lipedema fat tissue. More research is needed to characterize lipedema loose connective tissue structure in depth, as well as the form and function of blood and lymphatic vessels. Understanding the pathophysiology of the disease will allow healthcare providers to diagnose the disease and develop treatments.

**Keywords:** lipedema, symptoms, diagnosis, treatment, blood vessels, lymphatics

#### **1. Introduction**

Loose connective tissue disorders include lipedema, Dercum's disease (DD), familial multiple lipomatosis (FML) and multiple symmetric lipomatosis (MSL). All these disorders share many similarities with lipedema including painful lipomas, obesity, fibrosis, a risk of developing lymphedema and difficulty in losing the abnormal fat through diet and exercise. There are clinical characteristics specific for lipedema, including the onset of the disease, fat location and associated health issues (**Table 1**) [1, 2].

Lipedema is often misdiagnosed as lifestyle-induced obesity that affects ~10% of women of European descent as well as other populations [3, 4]. Although both disorders are considered inflammatory diseases due to the presence of increased macrophages and hypertrophic adipocytes, there are significant differences between the two disorders. Among these is the location of the fat, primarily abdominal or spread widely over the body in obesity compared to the symmetric distribution in the lower extremities in lipedema, the texture of the skin (thin and soft in lipedema and thicker in obesity), easy bruising and pain upon the introduction of pressure in lipedema [5, 6].


#### **Table 1.**

*Characteristics of loose connective tissue disorders.*

The focus of this review will be on the disease of lipedema, different stages and types, diagnosis and treatment, pathogenesis and current research in the field.

#### **2. Lipedema**

Lipedema also referred to as lipedema, is a painful loose connective tissue disorder first described in 1940 by Allen and Hines [7]. Lipedema is characterized by symmetric enlargement of the buttocks, hips and legs due to deposition of loose connective tissue that includes fascia, adipocytes, immune cells and other structures; arms are also affected in 80% of patients [3, 4]. Feet are typically spared, but ankle cuffs are often noted in advanced stages of lipedema where the risk of lymphedema is also high [8, 9]. Patients with lipedema experience mobility issues, psychosocial distress, anxiety, eating disorders, sleep apnea and depression [1, 10].

Lipedema is considered a hormone-related disorder affecting almost exclusively women during puberty, childbirth or menopause. Case reports of men with lipedema have been described in literature. Men with lipedema have elevated estrogen level and low to absent testosterone levels resulting in cirrhosis, gynecomastia and hypogonadism [11–13]. While the exact etiopathogenesis of this disease is unknown [10, 14], many studies have demonstrated that inflammatory cells, hypertrophic adipocytes, abnormal blood vessels and lymphatic dysfunction are associated with tissue damage and development of a fibrotic disease [14–17].

**89**

*Lipedema: A Painful Adipose Tissue Disorder DOI: http://dx.doi.org/10.5772/intechopen.88632*

obesity due to fat involving more areas of the body.

Lipedema consists of three stages characterized by the texture of skin and tissue formation. Stage 1 involves smooth skin over pearl-sized nodules in a hypertrophic fat layer; Stage 2 has skin indentations over a hypertrophic fat structure of pearlto-apple-size masses; and Stage 3 includes pearl-sized nodules and much larger fat masses causing lobules of skin and fat to form mainly on the hips, thighs, and around the knees. Lymphedema, causing fluid accumulation in the limbs, may develop during any stage of lipedema and is referred to as lipo-lymphedema [1, 3, 10, 18, 19]. Healthcare providers often misdiagnose women with lipedema as they do not take into account the disproportionate size of the legs compared to trunk especially in Stage 1 and 2 along with the inability to lose fat from areas affected by lipedema. It is possible to confuse women with Stage 3 lipedema as having lifestyle-induced

In addition to stages of lipedema, lipedema is also characterized by types determined by the area of the body that is affected. There are five types of lipedema; types I, II, and III are the most common. In Type I, fat is deposited in the areas of the buttocks and hips resembling saddle bags. In Type II, fat extends to the knees from the buttocks area with the formation of folds of fat around the inside of the knee. In Type III, fat spreads all over the lower body from the hips to the ankles. In Type IV, upper arms are affected causing difficulty in lifting the arm and stress on the shoulder. In Type V, fat is restricted to the lower legs. It is worth noting that patients with lipedema can clinically present with a mixture of types [3, 10].

Pain, tenderness, bruising easily, symmetrical swelling of the legs, heaviness of affected limbs, burning sensations in the skin and fat, soft skin, negative stemmer's sign and hypermobile joints are among the common symptoms observed in lipedema patients [2, 3, 6, 13]. Hypermobility in women with has been reported to contribute to joint damage and increase the risk of cardiovascular disease as seen in Ehlers Danlos Syndrome-Hypermobility Type (EDS-HT) with Beighton score higher than 5 [2, 3, 20, 21]. Thus, hypermobility causes structural changes in lipedema tissue resulting in increased fibrosis, dysfunction of blood vessels and

Women with lipedema also experience emotional symptoms due to unexplained weight gain including embarrassment, anxiety and depression that impact their overall quality of life [22, 23]. Symptoms may progress in advanced stages of lipedema that might be associated with increased cardiovascular and renal diseases. A study conducted by Herbst el al. in 2015 provides a detailed list of symptoms

Diagnosis of lipedema involves a comprehensive physical exam based on the criteria listed by Wold and colleagues in 1951, [4] medical and surgical history, list of medications that might affect weight or fluid retention and family history. A physical examination includes assessment of the enlarged lower extremities carefully noting the texture of the affected areas such as velvety soft skin that can be found in hypermobility, nodular fat, pain when applying pressure, tenderness upon

**2.1 Stages of lipedema**

**2.2 Types of lipedema**

**2.3 Signs and symptoms**

accumulation of interstitial fluid.

experienced by lipedema patients [3].

**2.4 Diagnosis and treatment of lipedema**

#### **2.1 Stages of lipedema**

*Adipose Tissue - An Update*

Legs, arms, abdomen

Puberty; 3rd decade

common

Autosomal dominant; incomplete penetrance

*Characteristics of loose connective tissue disorders.*

Lipomas Yes Common Common in

Abnormal fat location

Diet-resistant

fat

Time fat change

Sex predominance

Lymphatic dysfunction

Associated conditions

Inheritance pattern

*Modified from Ref. [1].*

**Table 1.**

Prevalence Possibly

The focus of this review will be on the disease of lipedema, different stages and

Lipedema also referred to as lipedema, is a painful loose connective tissue disorder first described in 1940 by Allen and Hines [7]. Lipedema is characterized by symmetric enlargement of the buttocks, hips and legs due to deposition of loose connective tissue that includes fascia, adipocytes, immune cells and other structures; arms are also affected in 80% of patients [3, 4]. Feet are typically spared, but ankle cuffs are often noted in advanced stages of lipedema where the risk of lymphedema is also high [8, 9]. Patients with lipedema experience mobility issues, psychosocial distress, anxiety, eating disorders, sleep apnea and

Lipedema is considered a hormone-related disorder affecting almost exclusively women during puberty, childbirth or menopause. Case reports of men with lipedema have been described in literature. Men with lipedema have elevated estrogen level and low to absent testosterone levels resulting in cirrhosis, gynecomastia and hypogonadism [11–13]. While the exact etiopathogenesis of this disease is unknown [10, 14], many studies have demonstrated that inflammatory cells, hypertrophic adipocytes, abnormal blood vessels and lymphatic dysfunction are associated with tissue damage and development of a fibrotic

types, diagnosis and treatment, pathogenesis and current research in the field.

**Characteristic Lipedema DD MSL FML MSL**

Global Upper; can

Child-adult Adult; child

Painful fat Yes Yes Not usually Lipoma Not usually

Possibly common

diabetes

Autosomal dominant; sex-specific influence

Lymphedema Autoimmune;

be global

Yes Yes Yes Yes Yes

men

rare

Female Female Male Male = female Male

Yes Yes Yes Yes Yes

Arms, thighs, trunk, abdomen

Rare Rare Rare

neuropathy

Autosomal dominant

Neuropathy Moles;

Autosomal dominant or recessive

Common Common in

Child-adult Adult; child

men

rare

Neuropathy

Autosomal dominant or recessive

Upper; can be global

**88**

**2. Lipedema**

depression [1, 10].

disease [14–17].

Lipedema consists of three stages characterized by the texture of skin and tissue formation. Stage 1 involves smooth skin over pearl-sized nodules in a hypertrophic fat layer; Stage 2 has skin indentations over a hypertrophic fat structure of pearlto-apple-size masses; and Stage 3 includes pearl-sized nodules and much larger fat masses causing lobules of skin and fat to form mainly on the hips, thighs, and around the knees. Lymphedema, causing fluid accumulation in the limbs, may develop during any stage of lipedema and is referred to as lipo-lymphedema [1, 3, 10, 18, 19].

Healthcare providers often misdiagnose women with lipedema as they do not take into account the disproportionate size of the legs compared to trunk especially in Stage 1 and 2 along with the inability to lose fat from areas affected by lipedema. It is possible to confuse women with Stage 3 lipedema as having lifestyle-induced obesity due to fat involving more areas of the body.

#### **2.2 Types of lipedema**

In addition to stages of lipedema, lipedema is also characterized by types determined by the area of the body that is affected. There are five types of lipedema; types I, II, and III are the most common. In Type I, fat is deposited in the areas of the buttocks and hips resembling saddle bags. In Type II, fat extends to the knees from the buttocks area with the formation of folds of fat around the inside of the knee. In Type III, fat spreads all over the lower body from the hips to the ankles. In Type IV, upper arms are affected causing difficulty in lifting the arm and stress on the shoulder. In Type V, fat is restricted to the lower legs. It is worth noting that patients with lipedema can clinically present with a mixture of types [3, 10].

#### **2.3 Signs and symptoms**

Pain, tenderness, bruising easily, symmetrical swelling of the legs, heaviness of affected limbs, burning sensations in the skin and fat, soft skin, negative stemmer's sign and hypermobile joints are among the common symptoms observed in lipedema patients [2, 3, 6, 13]. Hypermobility in women with has been reported to contribute to joint damage and increase the risk of cardiovascular disease as seen in Ehlers Danlos Syndrome-Hypermobility Type (EDS-HT) with Beighton score higher than 5 [2, 3, 20, 21]. Thus, hypermobility causes structural changes in lipedema tissue resulting in increased fibrosis, dysfunction of blood vessels and accumulation of interstitial fluid.

Women with lipedema also experience emotional symptoms due to unexplained weight gain including embarrassment, anxiety and depression that impact their overall quality of life [22, 23]. Symptoms may progress in advanced stages of lipedema that might be associated with increased cardiovascular and renal diseases. A study conducted by Herbst el al. in 2015 provides a detailed list of symptoms experienced by lipedema patients [3].

#### **2.4 Diagnosis and treatment of lipedema**

Diagnosis of lipedema involves a comprehensive physical exam based on the criteria listed by Wold and colleagues in 1951, [4] medical and surgical history, list of medications that might affect weight or fluid retention and family history. A physical examination includes assessment of the enlarged lower extremities carefully noting the texture of the affected areas such as velvety soft skin that can be found in hypermobility, nodular fat, pain when applying pressure, tenderness upon palpation and accumulation of fluid such as pitting or non-pitting edema which may indicate lymphedema [18, 24]. Bruising caused by increased capillary fragility [6], spider veins and telangiectasia showing on the surface of the skin due to venous insufficiency are also observed in lipedema patients [4, 10].

Although, there is no cure for lipedema, treatments like liposuction (tumescent and water jet) [25], complete decongestive therapy that includes manual lymphatic drainage [26, 27], compression garments, a healthy diet, physical activity, medications and supplements (statins, selenium, diosmin, amphetamines and butcher's broom) have been shown to reduce pain, improve lymphatic function, decrease leakage from blood vessels, lessen inflammation and fibrosis and maintain a healthy gut [24, 28–34].

Liposuction is by far the most effective treatment to decrease the fibrotic lipedema fat and thereby maintain mobility which is essential for the welfare of women living with lipedema [35–37]. Water jet-assisted liposuction has been proven to be as effective as tumescent liposuction. Damage to the lymph vessels has not been show as evidenced in a histological study conducted by Stutz et al. on lipoaspirates collected from lipedema patients [32]. Nevertheless, special care should be taken with lipo-lymphedema patients, where accumulated lymph and or fibrotic tissue should be removed first. Furthermore, follow-up and compression therapy are advised for successful and effective treatment.

Deep tissue massage has also been demonstrated to improve the quality of subcutaneous adipose tissue by decreasing pain, fibrosis and fat tissue in women with lipedema [29, 38].

Additionally, a healthy non-inflammatory diet is highly recommended, even though it will not reduce the lipedema tissue, but it might slow the progression of the disease by reducing inflammation and pain, lessen the swelling and ultimately improve quality of life. No one plan works for everyone but a ketogenic diet with low processed carbohydrate and mild physical exercises like walking, swimming, Pilates, yoga and other home excise programs are suggested by lipedema specialists. These activates will help the function of lymphatic pump and maintain a normal metabolism.

Finally, it is very important to detect and treat lipedema at early stages thus preventing the complications that might occur due to the progression of disease. These complications comprise eating disorders, sleep apnea, diabetes mellitus, arthritis, hypertension, cellulitis, cardiac and renal disease.

#### **3. Lipedema versus lymphedema**

There are distinctive criteria for lipedema which are absent in lymphedema including a negative Stemmer's sign, minimal pitting edema, thin skin, easy bruising, tenderness and pain [14, 39, 40]. Although lymphatic microaneurysms might develop in the later stages of lipedema leading to secondary lymphedema, imaging techniques like high-resolution cutaneous ultrasonography and magnetic resonance imaging showed no defects in the lymphatic system in early stages [24, 41–43]. Other methods have also been successfully used to differentiate lipedema from lymphedema which includes tissue dielectric constant and dual-energy X-ray absorptiometry techniques [44–48].

Dysfunction of lymphatic vessels results in accumulation of interstitial fluid (edema) in adipose tissues triggering inflammation by the recruitment of macrophages resulting in fibrosis and difficulty with weight loss. As a consequence, adipose tissue loses its elasticity suggesting that lipedema might be a connective tissue disorder [15, 49]. Studies have also indicated that edema might induce growth of lipedema fat as well as hypoxia resulting in adipocyte cell death [50].

**91**

*Lipedema: A Painful Adipose Tissue Disorder DOI: http://dx.doi.org/10.5772/intechopen.88632*

treating and following up of lipedema patients.

**4.2 Adipocytes, immune cells and blood vessels**

accumulation of interstitial fluid [15, 16, 54].

**4. Pathophysiology of the disease**

**4.1 Hormones**

Further, morphologic changes in lymphatic vessels and accumulation of interstitial fluid are present in some women with lipedema, with no change in transport of lymphatic fluid, which suggests these individuals might have a higher risk of progressing to lipo-lymphedema especially in advanced stages of lipedema [15, 51]. Accurate diagnosis of lipedema in association with lymphedema is essential for

Hormones, genetic factors, leaky blood vessels, dysfunctional lymphatics system, inflammation, hypertrophic adipocytes and interstitial thickening are among

Hormones play an essential role in the etiology of the lipedema, but how they affect the metabolism and function of adipocytes function is still unknown. Studies have shown that hormones, like estrogen and progesterone, have a direct effect on lipogenesis, insulin levels and adipose tissue distribution in the body. Dysregulation of hormonal levels lead to fat dysregulation, impairment of the lipogenesis-lipolysis mechanism, hypertension, insulin resistance and hyperinsulinemia [13, 52, 53]. Hormones might also have an impact on the nervous system which might explain the pain experienced by lipedema patients. Szél et al. hypothesized that alteration in estrogen (or estrogen receptors) maybe involved in the pathogenesis of lipedema by suggesting a link between accumulation of adipose tissue, imbalanced estrogen levels and inflammation of the peripheral and sympathetic nerves of the disease [13].

Lipedema fat tissue is characterized by hypertrophic adipocytes, inflammatory immune cells, dilation of subdermal blood and lymphatic vessels. We and others have shown a high number of infiltrating macrophages in lipedema adipose tissue detected by the CD68 marker and observed as around blood vessels or as crown-like structures surrounding necrotic adipocytes. In addition to macrophages, mast cells and T-lymphocytes were detected in hyper-vascular areas mainly around blood vessels in lipedema fat tissue which might contribute to capillary permeability and

An article published in 2004 by Taylor et al. showed that accumulation of mast cells in lipedema tissue contributed to increased interstitial fluid, deterioration of adipocytes and potentially elastic fiber fragmentation due to the release of elastase [55], confirming that lipedema is a connective tissue disorder. Adding to that, direct cellcell interaction between hypertrophic adipocyte and macrophages as well as secreted paracrine factors such as vascular endothelial growth factor (VEGF), a marker of angiogenesis, previously reported in the blood of women with lipedema [56] might be associated with increase in the number of blood vessels, dilation of capillaries, hypoxia, inflammation and tissue fibrosis found in lipedema patients [15, 18, 57].

**5. Is there a role of adipose-derived stem cells (ASC) in lipedema?**

Adipose tissue-derived stem cells are widely studied for their immunomodulatory, anti-inflammatory, anti-fibrotic, anti-apoptotic and pro-angiogenic effects

the factors that contribute to the pathogenesis of lipedema [10, 12, 15].

*Lipedema: A Painful Adipose Tissue Disorder DOI: http://dx.doi.org/10.5772/intechopen.88632*

Further, morphologic changes in lymphatic vessels and accumulation of interstitial fluid are present in some women with lipedema, with no change in transport of lymphatic fluid, which suggests these individuals might have a higher risk of progressing to lipo-lymphedema especially in advanced stages of lipedema [15, 51]. Accurate diagnosis of lipedema in association with lymphedema is essential for treating and following up of lipedema patients.

#### **4. Pathophysiology of the disease**

Hormones, genetic factors, leaky blood vessels, dysfunctional lymphatics system, inflammation, hypertrophic adipocytes and interstitial thickening are among the factors that contribute to the pathogenesis of lipedema [10, 12, 15].

#### **4.1 Hormones**

*Adipose Tissue - An Update*

healthy gut [24, 28–34].

with lipedema [29, 38].

palpation and accumulation of fluid such as pitting or non-pitting edema which may indicate lymphedema [18, 24]. Bruising caused by increased capillary fragility [6], spider veins and telangiectasia showing on the surface of the skin due to venous

Liposuction is by far the most effective treatment to decrease the fibrotic lipedema fat and thereby maintain mobility which is essential for the welfare of women living with lipedema [35–37]. Water jet-assisted liposuction has been proven to be as effective as tumescent liposuction. Damage to the lymph vessels has not been show as evidenced in a histological study conducted by Stutz et al. on lipoaspirates collected from lipedema patients [32]. Nevertheless, special care should be taken with lipo-lymphedema patients, where accumulated lymph and or fibrotic tissue should be removed first. Furthermore, follow-up and compression therapy

Deep tissue massage has also been demonstrated to improve the quality of subcutaneous adipose tissue by decreasing pain, fibrosis and fat tissue in women

Additionally, a healthy non-inflammatory diet is highly recommended, even though it will not reduce the lipedema tissue, but it might slow the progression of the disease by reducing inflammation and pain, lessen the swelling and ultimately improve quality of life. No one plan works for everyone but a ketogenic diet with low processed carbohydrate and mild physical exercises like walking, swimming, Pilates, yoga and other home excise programs are suggested by lipedema specialists. These activates will

Finally, it is very important to detect and treat lipedema at early stages thus preventing the complications that might occur due to the progression of disease. These complications comprise eating disorders, sleep apnea, diabetes mellitus, arthritis,

There are distinctive criteria for lipedema which are absent in lymphedema including a negative Stemmer's sign, minimal pitting edema, thin skin, easy bruising, tenderness and pain [14, 39, 40]. Although lymphatic microaneurysms might develop in the later stages of lipedema leading to secondary lymphedema, imaging techniques like high-resolution cutaneous ultrasonography and magnetic resonance imaging showed no defects in the lymphatic system in early stages [24, 41–43]. Other methods have also been successfully used to differentiate lipedema from lymphedema which includes tissue dielectric constant and dual-energy X-ray

Dysfunction of lymphatic vessels results in accumulation of interstitial fluid (edema) in adipose tissues triggering inflammation by the recruitment of macrophages resulting in fibrosis and difficulty with weight loss. As a consequence, adipose tissue loses its elasticity suggesting that lipedema might be a connective tissue disorder [15, 49]. Studies have also indicated that edema might induce growth

of lipedema fat as well as hypoxia resulting in adipocyte cell death [50].

help the function of lymphatic pump and maintain a normal metabolism.

Although, there is no cure for lipedema, treatments like liposuction (tumescent and water jet) [25], complete decongestive therapy that includes manual lymphatic drainage [26, 27], compression garments, a healthy diet, physical activity, medications and supplements (statins, selenium, diosmin, amphetamines and butcher's broom) have been shown to reduce pain, improve lymphatic function, decrease leakage from blood vessels, lessen inflammation and fibrosis and maintain a

insufficiency are also observed in lipedema patients [4, 10].

are advised for successful and effective treatment.

hypertension, cellulitis, cardiac and renal disease.

**3. Lipedema versus lymphedema**

absorptiometry techniques [44–48].

**90**

Hormones play an essential role in the etiology of the lipedema, but how they affect the metabolism and function of adipocytes function is still unknown. Studies have shown that hormones, like estrogen and progesterone, have a direct effect on lipogenesis, insulin levels and adipose tissue distribution in the body. Dysregulation of hormonal levels lead to fat dysregulation, impairment of the lipogenesis-lipolysis mechanism, hypertension, insulin resistance and hyperinsulinemia [13, 52, 53]. Hormones might also have an impact on the nervous system which might explain the pain experienced by lipedema patients. Szél et al. hypothesized that alteration in estrogen (or estrogen receptors) maybe involved in the pathogenesis of lipedema by suggesting a link between accumulation of adipose tissue, imbalanced estrogen levels and inflammation of the peripheral and sympathetic nerves of the disease [13].

#### **4.2 Adipocytes, immune cells and blood vessels**

Lipedema fat tissue is characterized by hypertrophic adipocytes, inflammatory immune cells, dilation of subdermal blood and lymphatic vessels. We and others have shown a high number of infiltrating macrophages in lipedema adipose tissue detected by the CD68 marker and observed as around blood vessels or as crown-like structures surrounding necrotic adipocytes. In addition to macrophages, mast cells and T-lymphocytes were detected in hyper-vascular areas mainly around blood vessels in lipedema fat tissue which might contribute to capillary permeability and accumulation of interstitial fluid [15, 16, 54].

An article published in 2004 by Taylor et al. showed that accumulation of mast cells in lipedema tissue contributed to increased interstitial fluid, deterioration of adipocytes and potentially elastic fiber fragmentation due to the release of elastase [55], confirming that lipedema is a connective tissue disorder. Adding to that, direct cellcell interaction between hypertrophic adipocyte and macrophages as well as secreted paracrine factors such as vascular endothelial growth factor (VEGF), a marker of angiogenesis, previously reported in the blood of women with lipedema [56] might be associated with increase in the number of blood vessels, dilation of capillaries, hypoxia, inflammation and tissue fibrosis found in lipedema patients [15, 18, 57].

#### **5. Is there a role of adipose-derived stem cells (ASC) in lipedema?**

Adipose tissue-derived stem cells are widely studied for their immunomodulatory, anti-inflammatory, anti-fibrotic, anti-apoptotic and pro-angiogenic effects

[58–60], but how ASCs contribute to the development of lipedema has not been investigated yet. Due to their high therapeutic potential, ASCs are now considered an indispensable tool in regenerative medicine [61–64]. Studies have shown the successful treatment with ASCs for many disease including graft-versus-host disease [65], wound healing [66], cardiovascular [67], inflammatory bowel disease [68], diabetes mellitus [69] and several injuries including kidney and spinal cord [70], bone and craniofacial reconstruction [71, 72], liver cirrhosis [73], multiple sclerosis [74]. In addition to their self-renewal ability, ASCs have the ability to differentiate into multiple lineages, including adipocytes, osteoblasts, chondrocytes, and endothelial cells [75, 76]. Thus, ASCs might play a role in lipedema adiposity by inducing the expansion and differentiation of progenitor adipose-derived stem/progenitor cells (pre-adipocytes) into mature adipocytes (hyperplasia). Suga el at. have shown an increase in proliferation of adipose-derived stem/progenitor cell proliferation using Ki67 and CD34 markers suggesting an increase in adipogenesis, hypoxia, and adipocyte necrosis, at least in one case [16].

Adding to that, inflammatory cytokines secreted by hypertrophic adipocytes and factors in the interstitial fluid could stimulate ASC differentiation into mature adipocytes. Alternatively, ASCs produce a plethora of pro- and anti-inflammatory cytokines that might contribute to angiogenesis and inflammation resulting in leaky and fragile blood vessels [77, 78]. Priglinger et al. have characterized lipedema ASCs isolated from liposuction samples and showed an increasing number of endothelial/pericytic cells using CD146 marker in lipedema patients compared to healthy individuals proposing that this increase might be a marker of repair of leaky blood and lymphatic vessels in lipedema tissues [54].

Although, ASCs might induce adipogenesis in lipedema an in-depth characterization of ASCs is required to confirm this theory. Otherwise, if ASCs prove to have anti-inflammatory, anti-fibrotic or pro-angiogenic effects, then they might be used to lessen tissue damage caused by leaky vessels; hence autologous treatment might be a promising tool for lipedema patients.

#### **6. Conclusion**

Lipedema is a painful fat disease that should be differentiated from obesity and lymphedema. It is the responsibility of the healthcare provider to determine the accurate diagnosis of the disease for successful treatment and management. Liposuction, hands-on therapy, exercise, and a healthy eating plan are recommended for lipedema patients. Although the etiology of lipedema is complicated, hypertrophic adipocytes, inflammatory cytokines, and macrophages, hypoxia, leaky vessels and accumulation of interstitial fluid contribute to the pathogenesis of the disease and may also help guide treatment.

**93**

**Author details**

Sara Al-Ghadban1

\*, Karen L. Herbst<sup>2</sup>

\*Address all correspondence to: sara.ghadban@gmail.com

School of Medicine, New Orleans, LA, USA

provided the original work is properly cited.

Arizona, Tucson, Arizona, USA

New Orleans, LA, USA

and Bruce A. Bunnell1,3

1 Center for Stem Cell Research and Regenerative Medicine, Tulane University

3 Department of Pharmacology, School of Medicine, Tulane University,

2 Department of Medicine and TREAT Program, College of Medicine, University of

© 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,

*Lipedema: A Painful Adipose Tissue Disorder DOI: http://dx.doi.org/10.5772/intechopen.88632*

#### **Acknowledgements**

This work was funded by a grant from the Lipedema Foundation.

#### **Conflict of interest**

The authors declare no conflict of interest.

*Lipedema: A Painful Adipose Tissue Disorder DOI: http://dx.doi.org/10.5772/intechopen.88632*

*Adipose Tissue - An Update*

[58–60], but how ASCs contribute to the development of lipedema has not been investigated yet. Due to their high therapeutic potential, ASCs are now considered an indispensable tool in regenerative medicine [61–64]. Studies have shown the successful treatment with ASCs for many disease including graft-versus-host disease [65], wound healing [66], cardiovascular [67], inflammatory bowel disease [68], diabetes mellitus [69] and several injuries including kidney and spinal cord [70], bone and craniofacial reconstruction [71, 72], liver cirrhosis [73], multiple sclerosis [74]. In addition to their self-renewal ability, ASCs have the ability to differentiate into multiple lineages, including adipocytes, osteoblasts, chondrocytes, and endothelial cells [75, 76]. Thus, ASCs might play a role in lipedema adiposity by inducing the expansion and differentiation of progenitor adipose-derived stem/progenitor cells (pre-adipocytes) into mature adipocytes (hyperplasia). Suga el at. have shown an increase in proliferation of adipose-derived stem/progenitor cell proliferation using Ki67 and CD34 markers suggesting an increase in

adipogenesis, hypoxia, and adipocyte necrosis, at least in one case [16].

and lymphatic vessels in lipedema tissues [54].

be a promising tool for lipedema patients.

the disease and may also help guide treatment.

The authors declare no conflict of interest.

**6. Conclusion**

**Acknowledgements**

**Conflict of interest**

Adding to that, inflammatory cytokines secreted by hypertrophic adipocytes and factors in the interstitial fluid could stimulate ASC differentiation into mature adipocytes. Alternatively, ASCs produce a plethora of pro- and anti-inflammatory cytokines that might contribute to angiogenesis and inflammation resulting in leaky and fragile blood vessels [77, 78]. Priglinger et al. have characterized lipedema ASCs isolated from liposuction samples and showed an increasing number of endothelial/pericytic cells using CD146 marker in lipedema patients compared to healthy individuals proposing that this increase might be a marker of repair of leaky blood

Although, ASCs might induce adipogenesis in lipedema an in-depth characterization of ASCs is required to confirm this theory. Otherwise, if ASCs prove to have anti-inflammatory, anti-fibrotic or pro-angiogenic effects, then they might be used to lessen tissue damage caused by leaky vessels; hence autologous treatment might

Lipedema is a painful fat disease that should be differentiated from obesity and lymphedema. It is the responsibility of the healthcare provider to determine the accurate diagnosis of the disease for successful treatment and management. Liposuction, hands-on therapy, exercise, and a healthy eating plan are recommended for lipedema patients. Although the etiology of lipedema is complicated, hypertrophic adipocytes, inflammatory cytokines, and macrophages, hypoxia, leaky vessels and accumulation of interstitial fluid contribute to the pathogenesis of

This work was funded by a grant from the Lipedema Foundation.

**92**

### **Author details**

Sara Al-Ghadban1 \*, Karen L. Herbst2 and Bruce A. Bunnell1,3

1 Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, New Orleans, LA, USA

2 Department of Medicine and TREAT Program, College of Medicine, University of Arizona, Tucson, Arizona, USA

3 Department of Pharmacology, School of Medicine, Tulane University, New Orleans, LA, USA

\*Address all correspondence to: sara.ghadban@gmail.com

© 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.

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*Adipose Tissue - An Update*

2015;**44**(3):121-132

2018;**8**(6):398-406

2018;**15**(6):921-928

clinical entity distinct from

Surgery. 1994;**94**(6):841-847

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[46] Bräutigam P et al. Analysis of lymphatic drainage in various forms of leg edema using two compartment

2007;**57**(2):S1-S3

2001;**34**(4):170-175

1997;**82**(4):411

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lymphoscintigraphy. Lymphology.

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[48] Birkballe S. Can tissue dielectric constant measurement aid in differentiating lymphoedema from lipoedema in women with swollen legs? British Journal of Dermatology.

[49] Williams A, Macewan I. Accurate diagnosis and self-care support for women with lipoedema. Practice Nursing. 2016;**27**(7):325-332

[50] Martin S, Edward MC, Peter C. Lymph makes you fat. Nature Genetics.

[51] Bilancini S et al. Functional lymphatic alterations in patients suffering from lipedema. Angiology.

of adipose tissue lipolysis by intravenous estrogens. Obesity.

2006;**14**(12):2163-2172

2004;**5**(4):197-216

2017;**19**(7):849-860

2004;**31**(2):205-209

[52] Van Pelt R et al. Acute modulation

[53] Mayes JS, Watson GH. Direct effects of sex steroid hormones on adipose tissues and obesity. Obesity Reviews.

[54] Priglinger E et al. The adipose tissue: Derived stromal vascular fraction cells from lipedema patients: Are they different? Cytotherapy.

[55] Taylor NE et al. Tumefactive lipedema with pseudoxanthoma elasticum-like microscopic changes. Journal of Cutaneous Pathology.

1998;**31**(2):43

s00238-019-01519-9

2014;**170**(1):96-103

2005;**37**(10):1023

1995;**46**(4):333-339

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[39] Shavit E, Wollina U, Alavi A. Lipoedema is not lymphoedema: A review of current literature. International Wound Journal.

[40] Rudkin G, Miller TA. Lipedema—A

lymphedema. Plastic and Reconstructive

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[57] Sun K et al. Fibrosis and adipose tissue dysfunction. Cell Metabolism. 2013;**18**(4):470-477

[58] Gimble MJ, Katz JA, Bunnell AB. Adipose-derived stem cells for regenerative medicine. Circulation Research. 2007;**100**(9):1249-1260

[59] Gimble JM et al. Concise review: Adipose-derived stromal vascular fraction cells and stem cells: Let's not get lost in translation. 2011: p. 749-754

[60] Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nature Reviews Immunology. 2008;**8**:726

[61] Frese L, Dijkman PE, Hoerstrup SP. Adipose tissue-derived stem cells in regenerative medicine. Transfusion Medicine and Hemotherapy. 2016;**43**(4):268-274

[62] Konno M et al. Adipose-derived mesenchymal stem cells and. Regenerative Medicine. 2013;**55**:309-318

[63] Ong WK, Sugii S. Adipose-derived stem cells: Fatty potentials for therapy. The International Journal of Biochemistry & Cell Biology. 2013;**45**(6):1083

[64] Schneider S. Adipose-derived mesenchymal stem cells from liposuction and resected fat are feasible sources for regenerative medicine. European Journal of Medical Research. 2017;**22**(1):17

[65] Amorin B et al. Mesenchymal stem cell therapy and acute graft-versushost disease: A review. Human Cell. 2014;**27**:137-150

[66] Li P, Guo X. A review: Therapeutic potential of adipose-derived stem

cells in cutaneous wound healing and regeneration. Stem Cell Research & Therapy. 2018;**9**(1)

[67] White IA et al. Mesenchymal stem cells in cardiology. Methods in Molecular Biology (Clifton, N.J.). 2016;**1416**:55

[68] De Francesco F et al. The role of adipose stem cells in inflammatory bowel disease: From biology to novel therapeutic strategies. Cancer Biology & Therapy; 2016. pp. 889-898

[69] Takahashi H et al. Regenerative and transplantation medicine: Cellular therapy using adipose tissue-derived mesenchymal stromal cells for type 1 diabetes mellitus. Journal of Clinical Medicine. 2019;**8**(2):249

[70] Crigna A et al. Stem/stromal cells for treatment of kidney injuries with focus on preclinical models. Frontiers in Medicine. 2018;**5**:179

[71] Paduano F et al. Adipose tissue as a strategic source of mesenchymal stem cells in bone regeneration: A topical review on the most promising craniomaxillofacial applications. International Journal of Molecular Sciences. 2017;**18**(10):2140

[72] Ciuffi S, Zonefrati R, Brandi ML. Adipose stem cells for bone tissue repair. Clinical Cases in Mineral and Bone Metabolism: The Official Journal of the Italian Society of Osteoporosis, Mineral Metabolism, and Skeletal Diseases. 2017;**14**(2):217

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**99**

death [6, 7].

**Chapter 7**

T2DM

**Abstract**

Mediators of Impaired

*Haya Al-Sulaiti, Alexander S. Dömling*

**1. Obesity-associated metabolic disease**

*and Mohamed A. Elrayess*

Adipogenesis in Obesity-

Associated Insulin Resistance and

Obesity has become a global health issue due to its high prevalence and associated comorbidities including insulin resistance (IR) and type 2 diabetes mellitus (T2DM). Obesity is associated with the expansion of adipose tissues through hypertrophy of mature adipocytes and differentiation of local preadipocytes in a process known as adipogenesis to store excess triacylglycerols (TAGs). Impairment of adipogenesis leads to ectopic fat deposition in skeletal muscles, liver, and kidneys, triggering IR in these tissues and increased risk of T2DM. Many factors contribute to impaired adipogenesis including obesity-associated mild chronic inflammation, oxidative stress, and fatty acid signaling. This review summarizes recent literature covering mediators of impaired adipogenesis and underlying molecular pathways.

**Keywords:** adipogenesis, mediators, inflammation, oxidative stress, fatty acids

Rapidly changing lifestyle, accompanied by consumption of excess energy in the form of a calorie-rich high-fat diet, lower voluntary activity, and increased exposure to environmental pollutants, have led to an exponential rise in noncommunicable metabolic diseases [1]. A key component of chronic metabolic diseases is obesity that has become a global health problem associated with a range of comorbidities including insulin resistance and type 2 T2DM [2], coronary artery disease (CAD) [3], nonalcoholic fatty liver [4], cancers [5], and elevated risk of premature

Adipose tissue is an endocrine organ that responds to obesity by secreting elevated quantities of free fatty acids, adipokines, and proinflammatory cytokines, triggering IR and risk of T2DM [8]. Obesity is also characterized by increased adiposity mediated by enlarged size of mature adipocytes (hypertrophy) and elevated number of newly recruited adipocytes (hyperplasia) [9–12]. Adipose tissue dysfunction is characterized by adipocyte hypertrophy, mild chronic inflammation, and oxidative stress, causing reduced ability to generate new adipocytes from the undifferentiated precursors (preadipocytes). The impaired adipogenesis increases risk of IR and T2DM by triggering ectopic fat deposition in nonadipose tissues

#### **Chapter 7**

*Adipose Tissue - An Update*

of multiple sclerosis. Journal of Neuroinflammation. 2018;**15**(1):77

adipose tissue-derived stromal/ stem cells: A joint statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT). Cytotherapy.

2013;**15**(6):641

2008;**45**(2):115-120

[75] Bourin P et al. Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded

[76] Bunnell BA et al. Adipose-derived stem cells: Isolation, expansion and differentiation. Methods.

mechanisms of mesenchymal stem cells in tissue repair. Methods in Molecular Biology (Clifton, N.J.). 2016;**1416**:123

[77] Gnecchi M et al. Paracrine

[78] Rehman JJ et al. Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation: Journal of the American Heart Association. 2004;**109**(10):1292-1298

**98**

## Mediators of Impaired Adipogenesis in Obesity-Associated Insulin Resistance and T2DM

*Haya Al-Sulaiti, Alexander S. Dömling and Mohamed A. Elrayess*

#### **Abstract**

Obesity has become a global health issue due to its high prevalence and associated comorbidities including insulin resistance (IR) and type 2 diabetes mellitus (T2DM). Obesity is associated with the expansion of adipose tissues through hypertrophy of mature adipocytes and differentiation of local preadipocytes in a process known as adipogenesis to store excess triacylglycerols (TAGs). Impairment of adipogenesis leads to ectopic fat deposition in skeletal muscles, liver, and kidneys, triggering IR in these tissues and increased risk of T2DM. Many factors contribute to impaired adipogenesis including obesity-associated mild chronic inflammation, oxidative stress, and fatty acid signaling. This review summarizes recent literature covering mediators of impaired adipogenesis and underlying molecular pathways.

**Keywords:** adipogenesis, mediators, inflammation, oxidative stress, fatty acids

#### **1. Obesity-associated metabolic disease**

Rapidly changing lifestyle, accompanied by consumption of excess energy in the form of a calorie-rich high-fat diet, lower voluntary activity, and increased exposure to environmental pollutants, have led to an exponential rise in noncommunicable metabolic diseases [1]. A key component of chronic metabolic diseases is obesity that has become a global health problem associated with a range of comorbidities including insulin resistance and type 2 T2DM [2], coronary artery disease (CAD) [3], nonalcoholic fatty liver [4], cancers [5], and elevated risk of premature death [6, 7].

Adipose tissue is an endocrine organ that responds to obesity by secreting elevated quantities of free fatty acids, adipokines, and proinflammatory cytokines, triggering IR and risk of T2DM [8]. Obesity is also characterized by increased adiposity mediated by enlarged size of mature adipocytes (hypertrophy) and elevated number of newly recruited adipocytes (hyperplasia) [9–12]. Adipose tissue dysfunction is characterized by adipocyte hypertrophy, mild chronic inflammation, and oxidative stress, causing reduced ability to generate new adipocytes from the undifferentiated precursors (preadipocytes). The impaired adipogenesis increases risk of IR and T2DM by triggering ectopic fat deposition in nonadipose tissues

and proinflammatory environment characterized by impaired secretion of various adipose-derived adipokines [13].

Obesity also represents an imbalance between the primary site of storing energy (the white fat) and the site that is specialized in energy expenditure (the brown fat) [14]. White adipocytes store fat in the form of triacylglycerols as a single fat lipid droplet that gets readily hydrolyzed by lipases when energy is needed. The resulting fatty acids are mobilized to other tissues to undergo fatty acid oxidation as a source of energy [15]. The imbalance between lipolysis and lipogenesis plays a crucial role in progression of metabolic disease including T2DM and nonalcoholic fatty liver disease [16]. The brown fat, on the other hand, uses the energy derived from fatty acid oxidation for heat generation [17].

Adipocyte hypertrophy is associated with increased uptake of excess TAGs, which triggers fat accumulation within the larger subcutaneous adipose tissue (SAT) [18–20]. SAT therefore plays a buffering role as it prohibits progression of obesity-associated pathologies [21]. However, the buffering capacity becomes limited as impairment of SAT expansion causes IR [22–24] as the excess fat are deposited in the visceral adipose tissue (VAT) as well as ectopically in the skeletal muscle, liver, kidney, and heart tissues [25]. This is augmented by the infiltration of macrophages and activation of the innate immune cells [26], which triggers hyperinsulinemia that inhibits lipolysis and activates lipoprotein lipase (LPL). This causes further hyperinsulinemia, hypertriglyceridemia, increased IR in these tissues [27], and risk of T2DM [28].

Although obesity is generally associated with these comorbidities, some obese individuals seem to be protected as they maintain insulin sensitivity (IS) and show lower hypertension and proatherogenic and inflammatory profiles than their equally obese pathogenic counterparts [29–32]. Investigating the underlying causes for this protective phenotype could potentially help obesity-associated pathogenicity. Although still unknown, various potential mechanisms were proposed to contribute to metabolically healthy obese (MHO) phenotype. These include lower visceral and ectopic fat deposition than subcutaneous fat accumulation due to efficient SAT adipogenesis, reduced inflammatory component in the adipose tissue, healthy levels of secreted adipokines, and more active lifestyle [33]. A genetic component was also suggested to interact with various environmental factors, although not yet determined [34]. Interestingly, lean diabetics also exhibit larger adipocytes than healthy individuals, perhaps due to impaired differentiation of preadipocytes but not a result of different frequencies of stromal vascular cells, lipolysis, or levels of inflammatory mediators [35]. Current therapeutic strategies focus on treating obesity-associated diseases instead of preventing the underlying mechanisms. Therefore, understanding the molecular mediators underlying the protective phenotype in MHO individuals could provide critical information to help individuals suffering from pathological obesity (PO). In this review, we aimed to understand the role of adipogenesis in obesity-associated IR and T2DM by screening 2317 articles investigating adipogenesis and mediators of impaired adipogenesis in PubMed with the aid of Rayyne, a systematic review web application [36].

#### **2. The role of adipogenesis in obesity-associated IR and T2DM**

The adipose tissue is a dynamic part of the endocrine system that plays a crucial role in maintaining energy balance and nutritional homeostasis [37]. Mature adipocytes constitute the most abundant distinctive cell type in the adipose tissue, occupying 90% of its volume [38]. Other components include leukocytes, macrophages, fibroblasts, endothelial cells, and preadipocytes, which constitute the

**101**

**Figure 1.**

*Schematic representation of the role of Wnt signaling in adipogenesis.*

*Mediators of Impaired Adipogenesis in Obesity-Associated Insulin Resistance and T2DM*

stromal vascular cells (4–6 million cells per gram of adipose tissue, half of which are

Obesity-induced adipocyte hypertrophy is associated with impaired recruitment and differentiation of preadipocytes. Despite their abundance, preadipocytes fail to undergo terminal differentiation into mature adipocytes via the activation of the canonical Wnt signaling [40]. Preadipocytes are produced by mesenchymal stem cells (MSCs) under the influence of different signaling molecules. The mature adipocytes secrete BMP4 that triggers preadipocyte differentiation by inducing the separation of Wnt1 inducible-signaling pathway protein 2 (WISP2) and zinc finger protein 423 (ZNF423), allowing ZNF423 to translocate into the nucleus and activate peroxisome proliferator-activated receptors (PPARγ) and downstream cascade including CCAAT/enhancer-binding proteins β (C/

BMP4 also plays an anti-inflammatory role by reducing tumor necrosis factor-α (TNF-α)-mediated proinflammatory cytokine induction in human adipocytes. Therefore, BMP4 plays a protective role against IR and T2DM [43]. Subsequently, PPARγ and C/EBPα activate preadipocyte differentiation and the expression of mature makers such as adiponectin, fatty acid-binding protein 4 (FABP4), glucose transporter type 4 (GLUT4), and LPL. The activation of PPARγ, therefore,

*DOI: http://dx.doi.org/10.5772/intechopen.88746*

EBPβ), δ, and α [41, 42] (**Figure 1**).

immune cells) [39].

*Mediators of Impaired Adipogenesis in Obesity-Associated Insulin Resistance and T2DM DOI: http://dx.doi.org/10.5772/intechopen.88746*

stromal vascular cells (4–6 million cells per gram of adipose tissue, half of which are immune cells) [39].

Obesity-induced adipocyte hypertrophy is associated with impaired recruitment and differentiation of preadipocytes. Despite their abundance, preadipocytes fail to undergo terminal differentiation into mature adipocytes via the activation of the canonical Wnt signaling [40]. Preadipocytes are produced by mesenchymal stem cells (MSCs) under the influence of different signaling molecules. The mature adipocytes secrete BMP4 that triggers preadipocyte differentiation by inducing the separation of Wnt1 inducible-signaling pathway protein 2 (WISP2) and zinc finger protein 423 (ZNF423), allowing ZNF423 to translocate into the nucleus and activate peroxisome proliferator-activated receptors (PPARγ) and downstream cascade including CCAAT/enhancer-binding proteins β (C/ EBPβ), δ, and α [41, 42] (**Figure 1**).

BMP4 also plays an anti-inflammatory role by reducing tumor necrosis factor-α (TNF-α)-mediated proinflammatory cytokine induction in human adipocytes. Therefore, BMP4 plays a protective role against IR and T2DM [43]. Subsequently, PPARγ and C/EBPα activate preadipocyte differentiation and the expression of mature makers such as adiponectin, fatty acid-binding protein 4 (FABP4), glucose transporter type 4 (GLUT4), and LPL. The activation of PPARγ, therefore,

**Figure 1.** *Schematic representation of the role of Wnt signaling in adipogenesis.*

*Adipose Tissue - An Update*

and risk of T2DM [28].

adipose-derived adipokines [13].

acid oxidation for heat generation [17].

and proinflammatory environment characterized by impaired secretion of various

Adipocyte hypertrophy is associated with increased uptake of excess TAGs, which triggers fat accumulation within the larger subcutaneous adipose tissue (SAT) [18–20]. SAT therefore plays a buffering role as it prohibits progression of obesity-associated pathologies [21]. However, the buffering capacity becomes limited as impairment of SAT expansion causes IR [22–24] as the excess fat are deposited in the visceral adipose tissue (VAT) as well as ectopically in the skeletal muscle, liver, kidney, and heart tissues [25]. This is augmented by the infiltration of macrophages and activation of the innate immune cells [26], which triggers hyperinsulinemia that inhibits lipolysis and activates lipoprotein lipase (LPL). This causes further hyperinsulinemia, hypertriglyceridemia, increased IR in these tissues [27],

Although obesity is generally associated with these comorbidities, some obese

individuals seem to be protected as they maintain insulin sensitivity (IS) and show lower hypertension and proatherogenic and inflammatory profiles than their equally obese pathogenic counterparts [29–32]. Investigating the underlying causes for this protective phenotype could potentially help obesity-associated pathogenicity. Although still unknown, various potential mechanisms were proposed to contribute to metabolically healthy obese (MHO) phenotype. These include lower visceral and ectopic fat deposition than subcutaneous fat accumulation due to efficient SAT adipogenesis, reduced inflammatory component in the adipose tissue, healthy levels of secreted adipokines, and more active lifestyle [33]. A genetic component was also suggested to interact with various environmental factors, although not yet determined [34]. Interestingly, lean diabetics also exhibit larger adipocytes than healthy individuals, perhaps due to impaired differentiation of preadipocytes but not a result of different frequencies of stromal vascular cells, lipolysis, or levels of inflammatory mediators [35]. Current therapeutic strategies focus on treating obesity-associated diseases instead of preventing the underlying mechanisms. Therefore, understanding the molecular mediators underlying the protective phenotype in MHO individuals could provide critical information to help individuals suffering from pathological obesity (PO). In this review, we aimed to understand the role of adipogenesis in obesity-associated IR and T2DM by screening 2317 articles investigating adipogenesis and mediators of impaired adipogenesis in PubMed with the aid of Rayyne, a systematic review web application [36].

**2. The role of adipogenesis in obesity-associated IR and T2DM**

The adipose tissue is a dynamic part of the endocrine system that plays a crucial role in maintaining energy balance and nutritional homeostasis [37]. Mature adipocytes constitute the most abundant distinctive cell type in the adipose tissue, occupying 90% of its volume [38]. Other components include leukocytes, macrophages, fibroblasts, endothelial cells, and preadipocytes, which constitute the

Obesity also represents an imbalance between the primary site of storing energy (the white fat) and the site that is specialized in energy expenditure (the brown fat) [14]. White adipocytes store fat in the form of triacylglycerols as a single fat lipid droplet that gets readily hydrolyzed by lipases when energy is needed. The resulting fatty acids are mobilized to other tissues to undergo fatty acid oxidation as a source of energy [15]. The imbalance between lipolysis and lipogenesis plays a crucial role in progression of metabolic disease including T2DM and nonalcoholic fatty liver disease [16]. The brown fat, on the other hand, uses the energy derived from fatty

**100**

maintains IS and exhibits an anti-inflammatory function, whereas IR causes impaired adipogenesis and increased risk of T2DM [44, 45].

Insulin and downstream Akt signaling also play important roles as modulators of adipose tissue growth and adipogenesis as insulin activates glucose and free fatty acid uptake, inhibits lipolysis, and de novo fatty acid synthesis in adipocytes, and induces adipogenesis [46]. The transcription factor nuclear factor kappa-lightchain-enhancer of activated B cells (NF-κB) has been shown to induce energy expenditure and reduce adipose tissue growth, leading to prevention of dietary obesity and lowering adipogenesis, inflammation, and IR [47]. The inhibition of inhibitor of nuclear factor kappa-B kinase subunit β (IKKβ) in mice lowers highfat diet-induced adipogenesis and inflammation and protects from diet-induced obesity and IR [48]. MicroRNAs (miRNAs) have been also shown to play an important role in adipogenesis, IR, and inflammation as previously reviewed [49]. Tonicity-responsive enhancer-binding protein (TonEBP), a key transcription factor involved in cellular adaptation to hypertonic stress, has been suggested to influence macrophage activity, adipogenesis, and IS by inhibiting the epigenetic transition of PPARγ2 [50]. Protectin DX (PDX), a ω-3 fatty acid-derived proresolution mediator, was reported to reduce inflammation and IR via an AMPK-dependent pathway and suppress adipogenesis and lipid accumulation during 3T3-L1 differentiation [51].

We have recently shown that higher adipogenic capacity of preadipocytes isolated from SAT and VAT from MHO individuals than PO counterparts may be one of the underlying mechanisms for MHO protection due to a greater ability to store TAGs in the SAT depot. This process was shown to be influenced by inflammatory mediators, oxidative stress, and fatty acid signaling [45, 52–55].

#### **3. Mediators of impaired adipogenesis in IR and T2DM**

#### **3.1 Inflammatory mediators**

#### *3.1.1 Impaired adipogenesis in response to proinflammatory signals*

Obesity-associated comorbidities are mediated by chronic mild inflammation (**Figure 2**). Lipid-laden adipocytes produce increased levels of cytokines such as Interleukin 6 (IL-6), IL-β, TNF-α, monocyte chemoattractant protein-1 (MCP-1), and IL-8 [10, 56, 57] which can inhibit preadipocyte differentiation [21, 45]. The impaired adipogenesis is associated with stress of the endoplasmic reticulum (ER) and elevated expression of unfolded protein response (UPR), both can exacerbate the proinflammatory phenotype of preadipocytes and adipocytes [58]. The effect of proinflammatory phenotype varies among various fat depots. VAT is a more inflammatory tissue than SAT as it secretes higher levels of proinflammatory cytokines. Macrophage infiltration into adipose tissue is regulated through serum resistin and leptin in obese individuals with early metabolic dysfunction [59]. The presence of macrophages in VAT contributes significantly to this phonotype. The presence of macrophages in human SAT, on the other hand, is causally related to impaired preadipocyte differentiation, which in turn is associated with systemic IR [60, 61]. Adipocyte differentiation, therefore, was shown to be significantly lower in VAT than SAT. Macrophage depletion can reduce inflammatory cytokines and trigger adiponectin secretion from both SAT and VAT adipocytes, leading to the induction of preadipocyte differentiation in SAT, but not VAT. Additionally, a negative correlation between SAT adipogenesis, but not VAT, and systemic IR was observed [62]. Chronic systemic inflammation is also associated with elevated lipolysis in white adipose tissue and lipogenesis in nonadipose tissues, causing ectopic fat deposition

**103**

risk of IR [63].

**Figure 2.**

in hepatocytes [73].

*Mediators of Impaired Adipogenesis in Obesity-Associated Insulin Resistance and T2DM*

in nonadipose tissues and imbalance in free fatty acid homeostasis and increased

*Mediators of impaired adipogenesis in IR and T2DM. Most proinflammatory cytokines as well as some anti-inflammatory mediators can impair adipogenesis (1). Similarly, various mediators of oxidative stress can impact adipogenesis both positively and negatively depending on their structure (2). Fatty acid signaling plays a key role in adipogenesis but at various degrees depending on the composition of the fatty acids (3). Finally,* 

*various environmental factors can impact adipogenesis mostly negatively (4).*

Among the proinflammatory cytokines, IL-6 is produced by adipocytes, activated leukocytes, and endothelial cells [64] in obesity [65–68]. IL-6 shows a synergistic effect with other mediators of metabolic disease, collectively contributing to the progression of other obesity-associated comorbidities such as CAD and T2DM [64, 69]. IL-6 impairs the LPL function leading to increased levels of circulating fat [69, 70]. Moreover, obesity-associated increase in IL-6 is linked to reduced insulin-triggered glucose uptake [60, 61]. Previous reports have indicated that insulin treatment improves the glucose transport activity of adipocytes in T2DM [21] and lowers IL-6 and TNF-α levels [53]. Although the precise mechanisms of IL-6-associated IR is not well characterized, human adipocytes from IR individuals were shown to exhibit significantly higher IL-6 expression levels [45]. IL-6 impairs insulin action by inhibiting expression of insulin receptor, insulin receptor substrate-1 (IRS-1), and GLUT4 in human preadipocytes as well as 3T3-L1 adipocytes [45, 71]. Furthermore, IL-6 was shown to reduce IS through decrease in adiponectin expression and secretion [72] and via impairment of insulin signaling

Various other cytokines have been shown to impact adipogenesis [74]. The proinflammatory cytokines IL-1 β, TNF-α, and MCP1 can also influence the hyperplastic expansion of adipose tissue and impair adipogenesis [59]. IL-1β triggers a proinflammatory response in human adipose tissues, particularly in VAT depot. IL-1β also inhibits insulin signal transduction, leading to impaired IS in adipose tissue [75]. IL-1β and cyclooxygenase-2 (COX-2) play a detrimental role in adipose tissue dysfunction in obesity [76]. With obesity, levels of MCP-1 and TNF-α increase in VAT before macrophage infiltration, suggesting a highly proinflammatory

*DOI: http://dx.doi.org/10.5772/intechopen.88746*

*Mediators of Impaired Adipogenesis in Obesity-Associated Insulin Resistance and T2DM DOI: http://dx.doi.org/10.5772/intechopen.88746*

#### **Figure 2.**

*Adipose Tissue - An Update*

maintains IS and exhibits an anti-inflammatory function, whereas IR causes

Insulin and downstream Akt signaling also play important roles as modulators of adipose tissue growth and adipogenesis as insulin activates glucose and free fatty acid uptake, inhibits lipolysis, and de novo fatty acid synthesis in adipocytes, and induces adipogenesis [46]. The transcription factor nuclear factor kappa-lightchain-enhancer of activated B cells (NF-κB) has been shown to induce energy expenditure and reduce adipose tissue growth, leading to prevention of dietary obesity and lowering adipogenesis, inflammation, and IR [47]. The inhibition of inhibitor of nuclear factor kappa-B kinase subunit β (IKKβ) in mice lowers highfat diet-induced adipogenesis and inflammation and protects from diet-induced obesity and IR [48]. MicroRNAs (miRNAs) have been also shown to play an important role in adipogenesis, IR, and inflammation as previously reviewed [49]. Tonicity-responsive enhancer-binding protein (TonEBP), a key transcription factor involved in cellular adaptation to hypertonic stress, has been suggested to influence macrophage activity, adipogenesis, and IS by inhibiting the epigenetic transition of PPARγ2 [50]. Protectin DX (PDX), a ω-3 fatty acid-derived proresolution mediator, was reported to reduce inflammation and IR via an AMPK-dependent pathway and suppress adipogenesis and lipid accumulation during 3T3-L1 differentiation [51]. We have recently shown that higher adipogenic capacity of preadipocytes isolated from SAT and VAT from MHO individuals than PO counterparts may be one of the underlying mechanisms for MHO protection due to a greater ability to store TAGs in the SAT depot. This process was shown to be influenced by inflammatory

impaired adipogenesis and increased risk of T2DM [44, 45].

mediators, oxidative stress, and fatty acid signaling [45, 52–55].

**3. Mediators of impaired adipogenesis in IR and T2DM**

*3.1.1 Impaired adipogenesis in response to proinflammatory signals*

Obesity-associated comorbidities are mediated by chronic mild inflammation (**Figure 2**). Lipid-laden adipocytes produce increased levels of cytokines such as Interleukin 6 (IL-6), IL-β, TNF-α, monocyte chemoattractant protein-1 (MCP-1), and IL-8 [10, 56, 57] which can inhibit preadipocyte differentiation [21, 45]. The impaired adipogenesis is associated with stress of the endoplasmic reticulum (ER) and elevated expression of unfolded protein response (UPR), both can exacerbate the proinflammatory phenotype of preadipocytes and adipocytes [58]. The effect of proinflammatory phenotype varies among various fat depots. VAT is a more inflammatory tissue than SAT as it secretes higher levels of proinflammatory cytokines. Macrophage infiltration into adipose tissue is regulated through serum resistin and leptin in obese individuals with early metabolic dysfunction [59]. The presence of macrophages in VAT contributes significantly to this phonotype. The presence of macrophages in human SAT, on the other hand, is causally related to impaired preadipocyte differentiation, which in turn is associated with systemic IR [60, 61]. Adipocyte differentiation, therefore, was shown to be significantly lower in VAT than SAT. Macrophage depletion can reduce inflammatory cytokines and trigger adiponectin secretion from both SAT and VAT adipocytes, leading to the induction of preadipocyte differentiation in SAT, but not VAT. Additionally, a negative correlation between SAT adipogenesis, but not VAT, and systemic IR was observed [62]. Chronic systemic inflammation is also associated with elevated lipolysis in white adipose tissue and lipogenesis in nonadipose tissues, causing ectopic fat deposition

**3.1 Inflammatory mediators**

**102**

*Mediators of impaired adipogenesis in IR and T2DM. Most proinflammatory cytokines as well as some anti-inflammatory mediators can impair adipogenesis (1). Similarly, various mediators of oxidative stress can impact adipogenesis both positively and negatively depending on their structure (2). Fatty acid signaling plays a key role in adipogenesis but at various degrees depending on the composition of the fatty acids (3). Finally, various environmental factors can impact adipogenesis mostly negatively (4).*

in nonadipose tissues and imbalance in free fatty acid homeostasis and increased risk of IR [63].

Among the proinflammatory cytokines, IL-6 is produced by adipocytes, activated leukocytes, and endothelial cells [64] in obesity [65–68]. IL-6 shows a synergistic effect with other mediators of metabolic disease, collectively contributing to the progression of other obesity-associated comorbidities such as CAD and T2DM [64, 69]. IL-6 impairs the LPL function leading to increased levels of circulating fat [69, 70]. Moreover, obesity-associated increase in IL-6 is linked to reduced insulin-triggered glucose uptake [60, 61]. Previous reports have indicated that insulin treatment improves the glucose transport activity of adipocytes in T2DM [21] and lowers IL-6 and TNF-α levels [53]. Although the precise mechanisms of IL-6-associated IR is not well characterized, human adipocytes from IR individuals were shown to exhibit significantly higher IL-6 expression levels [45]. IL-6 impairs insulin action by inhibiting expression of insulin receptor, insulin receptor substrate-1 (IRS-1), and GLUT4 in human preadipocytes as well as 3T3-L1 adipocytes [45, 71]. Furthermore, IL-6 was shown to reduce IS through decrease in adiponectin expression and secretion [72] and via impairment of insulin signaling in hepatocytes [73].

Various other cytokines have been shown to impact adipogenesis [74]. The proinflammatory cytokines IL-1 β, TNF-α, and MCP1 can also influence the hyperplastic expansion of adipose tissue and impair adipogenesis [59]. IL-1β triggers a proinflammatory response in human adipose tissues, particularly in VAT depot. IL-1β also inhibits insulin signal transduction, leading to impaired IS in adipose tissue [75]. IL-1β and cyclooxygenase-2 (COX-2) play a detrimental role in adipose tissue dysfunction in obesity [76]. With obesity, levels of MCP-1 and TNF-α increase in VAT before macrophage infiltration, suggesting a highly proinflammatory

phenotype of the visceral depot prior to infiltration of immune cells and macrophage phenotype switch [77]. Unlike IL-6, IL-1 β, and TNF-α, MCP-1 and MCP-1-induced protein (MCPIP) were shown to induce adipogenesis. Treatment of reactive oxygen species (ROS) inhibitor, apocynin, reduced the MCPIP-triggered adipogenesis [78]. Other cytokines involved in adipogenesis include interferon-γ (IFN-γ), a central mediator of macrophage function. Compared to obese wild-type control animals, obese IFN-γ knockouts exhibit better IS, smaller adipocyte size, and lower cytokine expression [79].

#### *3.1.2 Impaired adipogenesis in response to anti-inflammatory signals*

Contrary to the notion that inflammation plays a negative role in metabolism, some studies suggest that proinflammatory signals in the adipocytes are actually needed for functional adipose tissue homeostasis (**Figure 2**). Indeed, adipose tissue inflammation was shown in various animal models of adipose tissue-specific reduction of proinflammatory potential to be required as an adaptive response, allowing proper storage of excess fat and filtering of gut-derived endotoxins [80]. Additionally, various molecules with anti-inflammatory properties were shown to influence adipogenesis and risk of IR. Myokines, for example, secreted by skeletal muscle cells during exercise such as β-aminoisobutyric acid, can impair adipogenesis via activating AMPK signaling pathway and reducing levels of proinflammatory cytokines such as TNF-α [81]. Another example is the ubiquitin-editing enzyme A20 that impairs IL-6 secretion from adipocytes, leading to modulation of differentiation of MSCs [82]. The overexpression of A20 was also shown to reduce lipogenesis and adipogenesis via lowering levels of sterol regulatory element binding protein-1c (SREBP-1c) and aP2, causing lower fat accumulation in differentiated 3T3-L1 cells [83]. A third example is the nonerythropoietic EPO-derived peptide that plays an anti-inflammatory and anti-adipogenic roles in high-fat die mice with IR [84]. On the other hand, other anti-inflammatory molecules could rescue impaired adipogenesis. Glucose-dependent insulinotropic polypeptide (GIP), for example, is a potent activator of adipogenesis through modulation of inflammation in adipose tissue [85]. Additionally, the expression of neuronatin (Nnat), a proteolipid involved in neuronal development, in response to inflammation and dietary excess, has been suggested to play an important role in adipogenesis through lowering oxidative stress and inflammation [86].

#### **3.2 Oxidative stress**

Obesity leads to the accumulation of ROS, the hallmark of oxidative stress, in the adipose tissue causing impaired adipogenesis and increased risk of IR and T2DM. The balance between ROS generation and activation of endogenous antioxidants is crucial for cells undergoing adipogenesis [87] (**Figure 2**). The oxidative damage and changes in the expression of antioxidant enzymes with age are similar between SAT and VAT. However, preadipocytes from SAT are significantly more resistant than VAT-derived cells to cell death caused by oxidative stress [88]. Interestingly, within SAT and VAT depots, preadipocytes from insulin-sensitive obese subjects were more prone to oxidative damage than preadipocytes from equally obese insulin-resistant individuals [52, 53]. The depletion of ROS from adipose tissue in mice models of oxidative stress was associated with increased adipose tissue mass, lower ectopic fat deposition, and enhanced IS. Similarly, ROS accumulation limited the expansion of adipose tissue, leading to elevated ectopic fat accumulation and increased risk of IR [89]. Elevated ROS within the adipose tissue triggers lipid peroxidation [45] and accumulation of reactive aldehydes including the bioactive

**105**

process [110].

**3.3 Fatty acid signaling**

*Mediators of Impaired Adipogenesis in Obesity-Associated Insulin Resistance and T2DM*

lipid accumulation and levels of proinflammatory cytokines [99].

lipid peroxidation product 4-hydroxynonenal (4-HNE) [90]. Elevated 4-HNE causes damage of cell structure and function through the formation of the stable adducts 4-hydroxyalkenals with proteins, phospholipids, and DNA [91, 92]. Increased 4-HNE levels have been associated with impaired adipogenesis and IR [53, 93–96]. Another marker of oxidative damage is 8-hydroxy-2-deoxyguanosine (8-OHdG) which was recently shown to exert anti-inflammatory effects, by reducing TNF-αinduced IR in vitro. It was also shown to reduce adipose tissue mass in vivo through activation of adipose triglyceride lipase and lowering the expression of fatty acid synthase [97]. Levels of cholesterol oxidation-derived oxysterols increase in adipose tissues of T2DM patients and act as inhibitors of adipogenesis through activation of Wnt pathway [98]. Heme oxygenase (HO), a major cytoprotective enzyme, functions upstream of Wnt signaling and lowers lipogenesis and adipogenesis, decreasing

Conversely, ROS was also shown to enhance adipogenesis by lowering sirtuin 1 (Sirt1) expression [100, 101]. Heme-induced oxidative stress was shown to inhibit Sirt1, leading to increased adipogenesis [102]. The expression of deleted in bladder cancer protein 1 (DBC1), another inhibitor of the Sirt1, is reduced with obesity, leading to lower adipogenesis and VAT dysfunction [103]. Sirt3 plays a crucial role in mitochondrial function. Silencing of Sirt3 can cause adipocyte dysfunction which impairs adipogenesis and causes IR [104]. Nonselenocysteine-containing phospholipid hydroperoxide glutathione peroxidase (NPGPx) is a sensor of oxidative stress. Lack of NPGPx causes elevation in ROS and promotion of adipogenesis through ROS-dependent dimerization of protein kinase A regulatory subunits and activation of C/EBPβ [105]. Additional evidence suggesting ROS involvement in promotion of adipogenesis comes from antioxidant supplementation experiments where lower levels of ROS resulting from antioxidants contribute to adipose tissue dysfunction and IR [106]. Indeed, antioxidant supplementation exhibited a negative impact when used before induction of oxidative stress as a result of lowering physiological ROS levels because ROS plays a role as second messengers in adipogenesis, lipid metabolism, and insulin signaling [107]. For example, the supplementation with N-acetylcysteine, a known antioxidant and precursor of glutathione, was shown to reduce fat deposition during adipogenic differentiation of mouse fibroblasts [108]. Activation of beta-3 adrenergic receptor (β3-AR) enhances ROS accumulation in cultured adipocytes. Antioxidants enhance β3-ARtriggered mitochondrial ROS production, suggesting that chronic supplementation of antioxidants could indeed generate an elevation in oxidative stress associated with mitochondrial dysfunction in adipocyte [109]. On the other hand, glutathione depletion was shown to inhibit adipogenesis as the result of lowering cell proliferation during the initial mitotic clonal expansion of the adipocyte differentiation

The main role of adipocytes is TAG storage. Although TAGs do not function as signaling molecules per se, the lipid intermediates generated during lipogenesis and lipolysis influence intracellular insulin signaling and participate in progression of IR. These include free fatty acids, diacylglycerols (DAGs), and ceramides [111]. Lipolysis-driven efflux of fatty acids triggers TAG synthesis and causes stress of the ER and activation of June kinase pathway in the adipose tissues [112, 113]. This leads to an elevation in the levels of both DAGs and ceramides and progression of IR in adipocytes [114]. Ceramides were shown to influence lipid-mediated IR in muscles. Delta 4-desaturase, sphingolipid 1 (DEGS1) is a desaturase that mediates ceramide biosynthetic pathway. Ablation of DEGS1 in preadipocytes prevented

*DOI: http://dx.doi.org/10.5772/intechopen.88746*

#### *Mediators of Impaired Adipogenesis in Obesity-Associated Insulin Resistance and T2DM DOI: http://dx.doi.org/10.5772/intechopen.88746*

lipid peroxidation product 4-hydroxynonenal (4-HNE) [90]. Elevated 4-HNE causes damage of cell structure and function through the formation of the stable adducts 4-hydroxyalkenals with proteins, phospholipids, and DNA [91, 92]. Increased 4-HNE levels have been associated with impaired adipogenesis and IR [53, 93–96]. Another marker of oxidative damage is 8-hydroxy-2-deoxyguanosine (8-OHdG) which was recently shown to exert anti-inflammatory effects, by reducing TNF-αinduced IR in vitro. It was also shown to reduce adipose tissue mass in vivo through activation of adipose triglyceride lipase and lowering the expression of fatty acid synthase [97]. Levels of cholesterol oxidation-derived oxysterols increase in adipose tissues of T2DM patients and act as inhibitors of adipogenesis through activation of Wnt pathway [98]. Heme oxygenase (HO), a major cytoprotective enzyme, functions upstream of Wnt signaling and lowers lipogenesis and adipogenesis, decreasing lipid accumulation and levels of proinflammatory cytokines [99].

Conversely, ROS was also shown to enhance adipogenesis by lowering sirtuin 1 (Sirt1) expression [100, 101]. Heme-induced oxidative stress was shown to inhibit Sirt1, leading to increased adipogenesis [102]. The expression of deleted in bladder cancer protein 1 (DBC1), another inhibitor of the Sirt1, is reduced with obesity, leading to lower adipogenesis and VAT dysfunction [103]. Sirt3 plays a crucial role in mitochondrial function. Silencing of Sirt3 can cause adipocyte dysfunction which impairs adipogenesis and causes IR [104]. Nonselenocysteine-containing phospholipid hydroperoxide glutathione peroxidase (NPGPx) is a sensor of oxidative stress. Lack of NPGPx causes elevation in ROS and promotion of adipogenesis through ROS-dependent dimerization of protein kinase A regulatory subunits and activation of C/EBPβ [105]. Additional evidence suggesting ROS involvement in promotion of adipogenesis comes from antioxidant supplementation experiments where lower levels of ROS resulting from antioxidants contribute to adipose tissue dysfunction and IR [106]. Indeed, antioxidant supplementation exhibited a negative impact when used before induction of oxidative stress as a result of lowering physiological ROS levels because ROS plays a role as second messengers in adipogenesis, lipid metabolism, and insulin signaling [107]. For example, the supplementation with N-acetylcysteine, a known antioxidant and precursor of glutathione, was shown to reduce fat deposition during adipogenic differentiation of mouse fibroblasts [108]. Activation of beta-3 adrenergic receptor (β3-AR) enhances ROS accumulation in cultured adipocytes. Antioxidants enhance β3-ARtriggered mitochondrial ROS production, suggesting that chronic supplementation of antioxidants could indeed generate an elevation in oxidative stress associated with mitochondrial dysfunction in adipocyte [109]. On the other hand, glutathione depletion was shown to inhibit adipogenesis as the result of lowering cell proliferation during the initial mitotic clonal expansion of the adipocyte differentiation process [110].

#### **3.3 Fatty acid signaling**

The main role of adipocytes is TAG storage. Although TAGs do not function as signaling molecules per se, the lipid intermediates generated during lipogenesis and lipolysis influence intracellular insulin signaling and participate in progression of IR. These include free fatty acids, diacylglycerols (DAGs), and ceramides [111].

Lipolysis-driven efflux of fatty acids triggers TAG synthesis and causes stress of the ER and activation of June kinase pathway in the adipose tissues [112, 113]. This leads to an elevation in the levels of both DAGs and ceramides and progression of IR in adipocytes [114]. Ceramides were shown to influence lipid-mediated IR in muscles. Delta 4-desaturase, sphingolipid 1 (DEGS1) is a desaturase that mediates ceramide biosynthetic pathway. Ablation of DEGS1 in preadipocytes prevented

*Adipose Tissue - An Update*

and lower cytokine expression [79].

lowering oxidative stress and inflammation [86].

**3.2 Oxidative stress**

phenotype of the visceral depot prior to infiltration of immune cells and macrophage phenotype switch [77]. Unlike IL-6, IL-1 β, and TNF-α, MCP-1 and MCP-1-induced protein (MCPIP) were shown to induce adipogenesis. Treatment of reactive oxygen species (ROS) inhibitor, apocynin, reduced the MCPIP-triggered adipogenesis [78]. Other cytokines involved in adipogenesis include interferon-γ (IFN-γ), a central mediator of macrophage function. Compared to obese wild-type control animals, obese IFN-γ knockouts exhibit better IS, smaller adipocyte size,

Contrary to the notion that inflammation plays a negative role in metabolism, some studies suggest that proinflammatory signals in the adipocytes are actually needed for functional adipose tissue homeostasis (**Figure 2**). Indeed, adipose tissue inflammation was shown in various animal models of adipose tissue-specific reduction of proinflammatory potential to be required as an adaptive response, allowing proper storage of excess fat and filtering of gut-derived endotoxins [80]. Additionally, various molecules with anti-inflammatory properties were shown to influence adipogenesis and risk of IR. Myokines, for example, secreted by skeletal muscle cells during exercise such as β-aminoisobutyric acid, can impair adipogenesis via activating AMPK signaling pathway and reducing levels of proinflammatory cytokines such as TNF-α [81]. Another example is the ubiquitin-editing enzyme A20 that impairs IL-6 secretion from adipocytes, leading to modulation of differentiation of MSCs [82]. The overexpression of A20 was also shown to reduce lipogenesis and adipogenesis via lowering levels of sterol regulatory element binding protein-1c (SREBP-1c) and aP2, causing lower fat accumulation in differentiated 3T3-L1 cells [83]. A third example is the nonerythropoietic EPO-derived peptide that plays an anti-inflammatory and anti-adipogenic roles in high-fat die mice with IR [84]. On the other hand, other anti-inflammatory molecules could rescue impaired adipogenesis. Glucose-dependent insulinotropic polypeptide (GIP), for example, is a potent activator of adipogenesis through modulation of inflammation in adipose tissue [85]. Additionally, the expression of neuronatin (Nnat), a proteolipid involved in neuronal development, in response to inflammation and dietary excess, has been suggested to play an important role in adipogenesis through

Obesity leads to the accumulation of ROS, the hallmark of oxidative stress, in the adipose tissue causing impaired adipogenesis and increased risk of IR and T2DM. The balance between ROS generation and activation of endogenous antioxidants is crucial for cells undergoing adipogenesis [87] (**Figure 2**). The oxidative damage and changes in the expression of antioxidant enzymes with age are similar between SAT and VAT. However, preadipocytes from SAT are significantly more resistant than VAT-derived cells to cell death caused by oxidative stress [88]. Interestingly, within SAT and VAT depots, preadipocytes from insulin-sensitive obese subjects were more prone to oxidative damage than preadipocytes from equally obese insulin-resistant individuals [52, 53]. The depletion of ROS from adipose tissue in mice models of oxidative stress was associated with increased adipose tissue mass, lower ectopic fat deposition, and enhanced IS. Similarly, ROS accumulation limited the expansion of adipose tissue, leading to elevated ectopic fat accumulation and increased risk of IR [89]. Elevated ROS within the adipose tissue triggers lipid peroxidation [45] and accumulation of reactive aldehydes including the bioactive

*3.1.2 Impaired adipogenesis in response to anti-inflammatory signals*

**104**

adipogenesis and decreased lipid accumulation [115]. There are essential enzymes responsible for TAG hydrolysis including hormone-sensitive lipase (HSL), adipose triglyceride lipase (ATGL), and monoglyceride lipase (MGL) [116]. ATGL regulates lipolysis by transcription factor specificity protein 1 (Sp1). Insulin-mediated transcription of Sp1 is critical for this regulation. In mature adipocytes, PPARγ reverses transcriptional repression by Sp1 at the ATGL promoter, leading to stimulation of ATGL mRNA expression. During obesity and IR, the transcription of ATGL becomes downregulated. The extent of the downregulation depends on interactions between Sp1 and PPARγ [117].

A number of factors influence the function of fatty acids in regulating adipogenesis. The number of carbons and the position and number of double bounds are crucial determinants of properties of the fatty acids. Changes in fatty acids including elongation, desaturation, β-oxidation, peroxidation, and incorporation into phospo- and complex lipids can play an essential role in their metabolic function. Fatty acids and their metabolites can control protein expression involved in lipid and energy metabolism by influencing gene transcription, mRNA processing, and posttranslational modifications [118–121]. Most fatty acids activate all three members of the PPAR family [122–125]. Polyunsaturated fatty acids (PUFAs), except for erucic acid, are more potent stimulators of PPARγ than monounsaturated fatty acids (MUFAs) and saturated fatty acids [122–126] (**Figure 2**). The optimal binding affinity is reached with 16–20 carbon-containing compounds. DHA too was shown to stimulate PPARs [124]. Various studies have reported the beneficial effects of PUFAs on lipid-related human disorders [127–131], which largely depend on the structure of the fatty acids and their metabolic properties. PUFAs can inhibit lipogenic gene transcription by downregulating the expression SREBPs [132–135] and act as antagonists of liver X receptors (LXR) [136, 137] and as agonists for PPARs [122–124, 138, 139]. PUFAs, but not saturated or MUFAs, inhibit lipogenic genes by downregulating SREBP-1c. PPAR alpha plays an important role in metabolic adaptation to fasting by enhancing mitochondrial and peroxisomal fatty acid oxidation and ketogenesis [140]. Dietary PUFAs were also shown to stimulate expression of PPARα target genes, induce β-oxidation, and lower plasma TAGs [141–149]. Fatty acids can also play a role as modulators of kinase signaling pathways [150–155].

Arachidonic acid (AA), a polyunsaturated omega-6 fatty acid, is the major PUFA that has been implicated in the regulation of adipogenesis. Short exposure of 3T3-L1 mouse preadipocytes to AA triggers adipocyte differentiation, associated with increase in (FABP4/aP2). Calcium, protein kinase C, and ERK play critical role in this pathway through which AA induces the expression of adipocyte protein 2 (aP2) [156]. AA binds to PPAR-γ2 to stimulate GLUT4 expression in HepG2 cell line, exhibiting an alternative insulin-independent activation of GLUT4 [157]. AA cascade is then controlled by cyclooxygenases enzymes, lipoxygenases, and P450 epoxygenases. When AA is generated from plasma membrane via phospholipases and then metabolized by prostaglandin G/H synthase, different prostaglandins are produced, causing opposing effects on adipocyte differentiation. The proadipogenic effect of AA is mediated by prostaglandin product (prostacyclin) and is thus cyclooxygenase dependent [158–160]. Among prostaglandin classes, 15-deoxy-Δ12,14-prostaglandin J2 (15-d-PGJ2) was shown to be proadipogenic [161, 162]. On the other hand, prostaglandin F2α (PGF2α) was shown to exert anti-adipogenic effects in primary preadipocytes [163–165], 1246 cells [164], and 3T3-L1 cells [166–168]. The anti-adipogenic effect of PGF2α is mediated through prostaglandin F receptor-mediated elevation in intracellular calcium and DNA synthesis [168] and activation of MAPK, causing reduction in PPARγ phosphorylation [169]. The role of prostaglandin E2 (PGE2), the third main prostaglandin, in adipogenesis is controversial as PGE2 exhibits antilipolytic effect in mature adipocytes but shows

**107**

**Figure 3.**

*Mediators of Impaired Adipogenesis in Obesity-Associated Insulin Resistance and T2DM*

no effect on preadipocytes [170]. However, it was recently demonstrated that PGE2 inhibited adipogenesis of 3T3-L1 cells [171, 172]. Epoxyeicosatrienoic acids (EETs), AA metabolites, and AA-derived cytochrome P450 (CYP) epoxygenase metabolites exert anti-inflammatory effects in the vasculature. The expression of CYP2J, a member of P450 subfamily with a role in the bioactivation of AA in extrahepatic tissues, inhibits NF-κB and MAPK signaling pathways and activates of PPARγ, thus reducing IR and diabetic phenotype [173]. n-3 PUFAs, on the other hand, reduce adipose growth and play a role in adipogenesis in various rodent studies [174–183]. Medium-chain fatty acids (MCFAs) (C8–C10) bind the PPARγ ligand binding domain in vitro, causing full inhibition of phosphorylation of PPARγ by cyclindependent kinase 5 (cdk5) and reversal of IR in adipose tissue. MCFAs that bind PPARγ also inhibit thiazolidinedione-dependent adipogenesis in vitro [184]. On the other hand, MUFAs were shown to induce adipogenesis and enhance TAG accumulation in 3T3-L1 mouse preadipocytes. Levels of TAGs were greater in cells treated with c-22:1 than c18:1 and c-20:1. Among the c-22:1 fatty acids, c9–22:1 treatment showed higher fat accumulation, associated with increased expression of adipogenic and lipogenic transcription factors, such as PPARγ and C/EBPα and SREBP-1. However, c-20:1 FAs exhibited less effect than c-18:1 and c-22:1 [185]. Alpha-lipoic acid (ALA) activates insulin signaling pathway and exerts insulin-like properties in adipose and muscle cells. However, 3T3-L1 preadipocytes treated with LA exhibit lower insulin-induced differentiation by modulating activity and/or expression of various anti-adipogenic transcription factors mainly through activating the MAPK pathways that negatively regulate PPARγ and C/EBPα [141]. 10-oxo-12(Z)-octadecenoic acid, a linoleic acid metabolite, triggered adipocyte differentiation through PPARγ activation and elevated adiponectin secretion and insulin-triggered glucose uptake [142]. Dietary n-3 fatty acids showed more effective activation of PPARα in the liver of rodents [143–145] than n-6 fatty acids [146]. **Figure 3** summarizes the

*Adipogenic capacity of various fatty acids in 3T3L-1 cells in the absence or presence of 1 μg/ml insulin in differentiation medium (MDI) containing 0.5 mM isobutyl-1-methylxanthine and 1 μM dexamethasone in DMEM and 10% FBS. 100 μM palmitic acid (palm), oleic acid (ole), erucic acid, linoleic acid (LA), arachidonic acid (AA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or 1 μM rosiglitazone (rosi) dissolved in DMSO were added when differentiation was induced at day 0 and were present throughout* 

*the differentiation period (adapted from Madsen et al.) [147].*

*DOI: http://dx.doi.org/10.5772/intechopen.88746*

#### *Mediators of Impaired Adipogenesis in Obesity-Associated Insulin Resistance and T2DM DOI: http://dx.doi.org/10.5772/intechopen.88746*

no effect on preadipocytes [170]. However, it was recently demonstrated that PGE2 inhibited adipogenesis of 3T3-L1 cells [171, 172]. Epoxyeicosatrienoic acids (EETs), AA metabolites, and AA-derived cytochrome P450 (CYP) epoxygenase metabolites exert anti-inflammatory effects in the vasculature. The expression of CYP2J, a member of P450 subfamily with a role in the bioactivation of AA in extrahepatic tissues, inhibits NF-κB and MAPK signaling pathways and activates of PPARγ, thus reducing IR and diabetic phenotype [173]. n-3 PUFAs, on the other hand, reduce adipose growth and play a role in adipogenesis in various rodent studies [174–183].

Medium-chain fatty acids (MCFAs) (C8–C10) bind the PPARγ ligand binding domain in vitro, causing full inhibition of phosphorylation of PPARγ by cyclindependent kinase 5 (cdk5) and reversal of IR in adipose tissue. MCFAs that bind PPARγ also inhibit thiazolidinedione-dependent adipogenesis in vitro [184]. On the other hand, MUFAs were shown to induce adipogenesis and enhance TAG accumulation in 3T3-L1 mouse preadipocytes. Levels of TAGs were greater in cells treated with c-22:1 than c18:1 and c-20:1. Among the c-22:1 fatty acids, c9–22:1 treatment showed higher fat accumulation, associated with increased expression of adipogenic and lipogenic transcription factors, such as PPARγ and C/EBPα and SREBP-1. However, c-20:1 FAs exhibited less effect than c-18:1 and c-22:1 [185]. Alpha-lipoic acid (ALA) activates insulin signaling pathway and exerts insulin-like properties in adipose and muscle cells. However, 3T3-L1 preadipocytes treated with LA exhibit lower insulin-induced differentiation by modulating activity and/or expression of various anti-adipogenic transcription factors mainly through activating the MAPK pathways that negatively regulate PPARγ and C/EBPα [141]. 10-oxo-12(Z)-octadecenoic acid, a linoleic acid metabolite, triggered adipocyte differentiation through PPARγ activation and elevated adiponectin secretion and insulin-triggered glucose uptake [142]. Dietary n-3 fatty acids showed more effective activation of PPARα in the liver of rodents [143–145] than n-6 fatty acids [146]. **Figure 3** summarizes the

#### **Figure 3.**

*Adipose Tissue - An Update*

between Sp1 and PPARγ [117].

adipogenesis and decreased lipid accumulation [115]. There are essential enzymes responsible for TAG hydrolysis including hormone-sensitive lipase (HSL), adipose triglyceride lipase (ATGL), and monoglyceride lipase (MGL) [116]. ATGL regulates lipolysis by transcription factor specificity protein 1 (Sp1). Insulin-mediated transcription of Sp1 is critical for this regulation. In mature adipocytes, PPARγ reverses transcriptional repression by Sp1 at the ATGL promoter, leading to stimulation of ATGL mRNA expression. During obesity and IR, the transcription of ATGL becomes downregulated. The extent of the downregulation depends on interactions

A number of factors influence the function of fatty acids in regulating adipogenesis. The number of carbons and the position and number of double bounds are crucial determinants of properties of the fatty acids. Changes in fatty acids including elongation, desaturation, β-oxidation, peroxidation, and incorporation into phospo- and complex lipids can play an essential role in their metabolic function. Fatty acids and their metabolites can control protein expression involved in lipid and energy metabolism by influencing gene transcription, mRNA processing, and posttranslational modifications [118–121]. Most fatty acids activate all three members of the PPAR family [122–125]. Polyunsaturated fatty acids (PUFAs), except for erucic acid, are more potent stimulators of PPARγ than monounsaturated fatty acids (MUFAs) and saturated fatty acids [122–126] (**Figure 2**). The optimal binding affinity is reached with 16–20 carbon-containing compounds. DHA too was shown to stimulate PPARs [124]. Various studies have reported the beneficial effects of PUFAs on lipid-related human disorders [127–131], which largely depend on the structure of the fatty acids and their metabolic properties. PUFAs can inhibit lipogenic gene transcription by downregulating the expression SREBPs [132–135] and act as antagonists of liver X receptors (LXR) [136, 137] and as agonists for PPARs [122–124, 138, 139]. PUFAs, but not saturated or MUFAs, inhibit lipogenic genes by downregulating SREBP-1c. PPAR alpha plays an important role in metabolic adaptation to fasting by enhancing mitochondrial and peroxisomal fatty acid oxidation and ketogenesis [140]. Dietary PUFAs were also shown to stimulate expression of PPARα target genes, induce β-oxidation, and lower plasma TAGs [141–149]. Fatty acids can also play a role as modulators of kinase signaling pathways [150–155]. Arachidonic acid (AA), a polyunsaturated omega-6 fatty acid, is the major PUFA that has been implicated in the regulation of adipogenesis. Short exposure of 3T3-L1 mouse preadipocytes to AA triggers adipocyte differentiation, associated with increase in (FABP4/aP2). Calcium, protein kinase C, and ERK play critical role in this pathway through which AA induces the expression of adipocyte protein 2 (aP2) [156]. AA binds to PPAR-γ2 to stimulate GLUT4 expression in HepG2 cell line, exhibiting an alternative insulin-independent activation of GLUT4 [157]. AA cascade is then controlled by cyclooxygenases enzymes, lipoxygenases, and P450 epoxygenases. When AA is generated from plasma membrane via phospholipases and then metabolized by prostaglandin G/H synthase, different prostaglandins are produced, causing opposing effects on adipocyte differentiation. The proadipogenic effect of AA is mediated by prostaglandin product (prostacyclin) and is thus cyclooxygenase dependent [158–160]. Among prostaglandin classes, 15-deoxy-Δ12,14-prostaglandin J2 (15-d-PGJ2) was shown to be proadipogenic [161, 162]. On the other hand, prostaglandin F2α (PGF2α) was shown to exert anti-adipogenic effects in primary preadipocytes [163–165], 1246 cells [164], and 3T3-L1 cells [166–168]. The anti-adipogenic effect of PGF2α is mediated through prostaglandin F receptor-mediated elevation in intracellular calcium and DNA synthesis [168] and activation of MAPK, causing reduction in PPARγ phosphorylation [169]. The role of prostaglandin E2 (PGE2), the third main prostaglandin, in adipogenesis is controversial as PGE2 exhibits antilipolytic effect in mature adipocytes but shows

**106**

*Adipogenic capacity of various fatty acids in 3T3L-1 cells in the absence or presence of 1 μg/ml insulin in differentiation medium (MDI) containing 0.5 mM isobutyl-1-methylxanthine and 1 μM dexamethasone in DMEM and 10% FBS. 100 μM palmitic acid (palm), oleic acid (ole), erucic acid, linoleic acid (LA), arachidonic acid (AA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or 1 μM rosiglitazone (rosi) dissolved in DMSO were added when differentiation was induced at day 0 and were present throughout the differentiation period (adapted from Madsen et al.) [147].*

effect of various fatty acid species on the proadipogenic capacity of 3T3L-1 cells in the presence or absence of insulin (Madsen et al.) [147].

Lipidomics studies were performed to investigate differences between SAT and VAT depots. These studies have shown evidence of depot-specific enrichment of certain species of TAGs, glycerophospholipids, and sphingolipids and specific correlations between certain lipid species and body mass index, inflammation, and IS [148, 149]. We have recently shown in human SAT and omental (OM) adipose tissue biopsies from 64 obese individuals a number of TAGs that changed with increased risk IR and T2DM including C46:4, C48:5, C48:4, C38:1, C50:3, C40:2, C56:3, C56:4, C56:7, and C58:7. Enrichment analysis showed C12:0 fatty acid to be associated with TAGs that are least abundant in T2DM. Our data also indicated that C18:3 was present in both depleted and enriched TAGs in T2DM [55]. Secretion of interleukin IL-6 was found to be significantly lower after treatment with C18:2, C22:6, and C16:0 through blocking NF-κB and activating PPARγ [186]. Our data also showed positive correlations between C56:4 and C57:4, both containing C18:2 and C16:0, with SC adipogenic capacity. OM adipogenic capacity was associated with C49:1, C38:0, and C56:2, containing C16:0, C18:1, and C14:0 [55]. **Table 1** summarizes a list of


**109**

*Mediators of Impaired Adipogenesis in Obesity-Associated Insulin Resistance and T2DM*

TAGs associated with SAT and OM adipogenic capacity. These fatty acids were reported to stimulate adipogenesis in rodents [187–191] and potentially in human

Various types of environmental factors were shown to influence adipogenesis. These include environmental pollutants. Among the environmental pollutants, polybrominated diphenyl ethers (PBDEs) represent a widely used type of flame retardants in commercial products and a main source of environmental contaminants. PBDEs accumulate in adipose tissue, potentially changing its endocrine function causing elevation in the risk of IR. We have previously shown that specific congeners of PBDEs (28, 47, 99, and 153) were predominant in VAT from obese individuals and that PBDEs 99, 28, and 47 were elevated in obese IR compared to obese IS. Treatment of human VAT-derived preadipocytes from obese IS individuals with PBDE28 inhibited insulin signaling and reduced adipogenesis [54]. In addition to PBDEs, evidence linking accumulation of other persistent organic pollutants (POPs) and risk of IR and T2DM was previously described [54, 192]. Additionally, the association between inorganic arsenic exposure and the risk of T2DM and obesity was previously reported [193]. Arsenic-induced T2DM is suggested to be mediated by inflammation, oxidative stress, and apoptosis, playing a significant role in the pathogenesis of obesity. Arsenic inhibits adipogenesis and enhances lipolysis, leading to obesity. Other reports have suggested that arsenic may induce lipodystrophy [193]. Another evidence suggests that uremic toxin-treated 3T3-L1 cells and MSC-derived adipocytes exhibit impaired adipogenesis and apoptosis through activation of the Na/K-ATPase/ROS amplification cycle [194]. Other types of environmental pollutants include organotins, widely used antifouling biocides for ships and fishing nets, play a role as endocrine disruptors as they bind to PPARγ/ RXRα, induce adipogenesis, and repress inflammatory genes in different mamma-

The pathology of obesity-associated IR and T2DM involves ectopic fat deposition in response to elevated energy intake and poor fat storage. The latter is due to impaired adipogenesis as newly recruited preadipocytes become unable to differentiate into fully functional adipocytes. This review presents several factors that influence adipogenesis in pathological obesity including inflammatory mediators, oxidative stress, fatty acid signaling, and other environmental factors. Most proinflammatory cytokines such as IL-6, IL-1β, TNF-α, IL-8, and IFNγ as well as some anti-inflammatory mediators including β-aminoisobutyric acid, A20 enzyme, and EPO have been shown to impair adipogenesis, leading to adipocyte hypertrophy, ectopic fat accumulation, and increased risk of IR and T2DM. However, basal level of adipose tissue inflammation has been shown to be required for normal adipogenesis and functional adipose tissue homeostasis. Similarly, various mediators of oxidative stress were shown to impact adipogenesis positively such as lipid peroxidation product 4-HNE and negatively such as the marker of oxidative damage 8-OHdG. Targeting lipid peroxidation products was shown to reverse impairment of adipogenesis and sustain IS. However, complete depletion of oxidative stress could also lead to impairment of adipogenesis as basal oxidative stress was shown to be required for normal adipogenesis. Fatty acid signaling also plays a very

*DOI: http://dx.doi.org/10.5772/intechopen.88746*

preadipocytes.

lian cells [195].

**5. Conclusion**

**4. Environmental factors**

**Table 1.** *List of TAGs associated with IR, SC, and OM adipogenic capacity.* TAGs associated with SAT and OM adipogenic capacity. These fatty acids were reported to stimulate adipogenesis in rodents [187–191] and potentially in human preadipocytes.

### **4. Environmental factors**

*Adipose Tissue - An Update*

**Metabolic trait**

SC adipogenic

OM adipogenic

effect of various fatty acid species on the proadipogenic capacity of 3T3L-1 cells in

*R***<sup>2</sup> Importance TAG MW Fatty acid** 

0.9 0.16 C58:10 926.8 C18:2, C18:2,

0.16 C56:4 910.8 C18:1, C18:2,

0.14 C57:4 924.7 C22:0, C19:4,

0.09 C40:1 692.7 C18:1, C16:0,

0.22 C38:1 664.7 C18:1, C16:0,

0.14 C49:1 818.7 C18:1, C17:0,

0.11 C56:1 916.8 C18:0, C18:0,

0.09 C54:0 890.8 C18:0, C18:0,

0.06 C38:0 666.7 C10:0,

0.05 C56:2 914.8 C18:1, C18:1,

0.04 C51:1 846.7 C18:1, C15:0,

*List of TAGs associated with IR, SC, and OM adipogenic capacity.*

0.08 C60:1 970.8 C24:0,

1 0.18 C48:1 804.8 C18:0, C16:1,

**composition**

C22:6

C20:1

C16:0

C6:0

C24:0, C18:1

C4:0

C14:0

C14:0

C20:1

C18:0

C14:0, C14:0

C20:0

C18:0

**Fatty acid identities**

Linoleic acid, linoleic acid, docosahexaenoic acid

Oleic acid, linoleic acid, gadoleic acid

Behenic acid, C19:4, palmitic acid

Oleic acid, palmitic acid, caproic acid

Lignoceric acid, oleic acid

Oleic acid, palmitic acid, butyric acid

Stearic acid, palmitoleic acid, myristic acid

Oleic acid, heptadecanoic acid, myristic acid

Stearic acid, stearic acid, gadoleic

Stearic acid, stearic acid

Capric acid, myristic acid

Oleic acid, oleic acid, arachidic acid

Oleic acid, pentadecanoic acid, stearic acid

Lipidomics studies were performed to investigate differences between SAT and VAT depots. These studies have shown evidence of depot-specific enrichment of certain species of TAGs, glycerophospholipids, and sphingolipids and specific correlations between certain lipid species and body mass index, inflammation, and IS [148, 149]. We have recently shown in human SAT and omental (OM) adipose tissue biopsies from 64 obese individuals a number of TAGs that changed with increased risk IR and T2DM including C46:4, C48:5, C48:4, C38:1, C50:3, C40:2, C56:3, C56:4, C56:7, and C58:7. Enrichment analysis showed C12:0 fatty acid to be associated with TAGs that are least abundant in T2DM. Our data also indicated that C18:3 was present in both depleted and enriched TAGs in T2DM [55]. Secretion of interleukin IL-6 was found to be significantly lower after treatment with C18:2, C22:6, and C16:0 through blocking NF-κB and activating PPARγ [186]. Our data also showed positive correlations between C56:4 and C57:4, both containing C18:2 and C16:0, with SC adipogenic capacity. OM adipogenic capacity was associated with C49:1, C38:0, and C56:2, containing C16:0, C18:1, and C14:0 [55]. **Table 1** summarizes a list of

the presence or absence of insulin (Madsen et al.) [147].

**108**

**Table 1.**

Various types of environmental factors were shown to influence adipogenesis. These include environmental pollutants. Among the environmental pollutants, polybrominated diphenyl ethers (PBDEs) represent a widely used type of flame retardants in commercial products and a main source of environmental contaminants. PBDEs accumulate in adipose tissue, potentially changing its endocrine function causing elevation in the risk of IR. We have previously shown that specific congeners of PBDEs (28, 47, 99, and 153) were predominant in VAT from obese individuals and that PBDEs 99, 28, and 47 were elevated in obese IR compared to obese IS. Treatment of human VAT-derived preadipocytes from obese IS individuals with PBDE28 inhibited insulin signaling and reduced adipogenesis [54]. In addition to PBDEs, evidence linking accumulation of other persistent organic pollutants (POPs) and risk of IR and T2DM was previously described [54, 192]. Additionally, the association between inorganic arsenic exposure and the risk of T2DM and obesity was previously reported [193]. Arsenic-induced T2DM is suggested to be mediated by inflammation, oxidative stress, and apoptosis, playing a significant role in the pathogenesis of obesity. Arsenic inhibits adipogenesis and enhances lipolysis, leading to obesity. Other reports have suggested that arsenic may induce lipodystrophy [193]. Another evidence suggests that uremic toxin-treated 3T3-L1 cells and MSC-derived adipocytes exhibit impaired adipogenesis and apoptosis through activation of the Na/K-ATPase/ROS amplification cycle [194]. Other types of environmental pollutants include organotins, widely used antifouling biocides for ships and fishing nets, play a role as endocrine disruptors as they bind to PPARγ/ RXRα, induce adipogenesis, and repress inflammatory genes in different mammalian cells [195].

#### **5. Conclusion**

The pathology of obesity-associated IR and T2DM involves ectopic fat deposition in response to elevated energy intake and poor fat storage. The latter is due to impaired adipogenesis as newly recruited preadipocytes become unable to differentiate into fully functional adipocytes. This review presents several factors that influence adipogenesis in pathological obesity including inflammatory mediators, oxidative stress, fatty acid signaling, and other environmental factors. Most proinflammatory cytokines such as IL-6, IL-1β, TNF-α, IL-8, and IFNγ as well as some anti-inflammatory mediators including β-aminoisobutyric acid, A20 enzyme, and EPO have been shown to impair adipogenesis, leading to adipocyte hypertrophy, ectopic fat accumulation, and increased risk of IR and T2DM. However, basal level of adipose tissue inflammation has been shown to be required for normal adipogenesis and functional adipose tissue homeostasis. Similarly, various mediators of oxidative stress were shown to impact adipogenesis positively such as lipid peroxidation product 4-HNE and negatively such as the marker of oxidative damage 8-OHdG. Targeting lipid peroxidation products was shown to reverse impairment of adipogenesis and sustain IS. However, complete depletion of oxidative stress could also lead to impairment of adipogenesis as basal oxidative stress was shown to be required for normal adipogenesis. Fatty acid signaling also plays a very

important role in adipogenesis as various fatty acid species such as PUFAs, MUFAs, and MCFAs were shown to regulate preadipocyte differentiation at various degrees depending on their composition. Finally, various environmental factors were suggested to impact adipogenesis, mainly through triggering inflammation and oxidative stress, leading to impairment of adipogenesis and increased risk of IR.

### **Competing interests**

The authors declare that they have no competing interests.

### **Authors' contributions**

All authors participated in reviewing the literature and preparing and approving the manuscript. MAE is responsible for the integrity of the work as a whole.

### **Abbreviations**


**111**

*Mediators of Impaired Adipogenesis in Obesity-Associated Insulin Resistance and T2DM*

NF-kappa-B nuclear factor kappa-light-chain enhancer of activated B cells

NPGPx nonselenocysteine-containing phospholipid hydroperoxide gluta-

*DOI: http://dx.doi.org/10.5772/intechopen.88746*

MGL monoglyceride lipase MHO metabolically healthy obese

OM omental adipose tissue

PUFAs polyunsaturated fatty acids ROS reactive oxygen species

SAT subcutaneous adipose tissue

UPR unfolded protein response VAT visceral adipose tissue

ZNF423 zinc finger protein 423 β3-AR beta-3 adrenergic receptor MSCs mesenchymal stem cells Ap2 adipocyte protein 2 CYP cytochrome P450 ALA alpha-lipoic acid

miRNAs microRNAs

Nnat neurontin

Ole oleic acid

Palm palmitic acid PBDEs diphenyl ethers PDX protectin DX PGE2 prostaglandin E2 PGF2α prostaglandin F2α PO pathological obesity POPs organic pollutants

Rosi rosiglitazone

T2DM type 2 diabetes

Sirt1 sirtuin 1

MDI insulin in differentiation medium

thione peroxidase

PPAR peroxisome proliferator-activated receptors

Sp1 transcription factor specificity protein 1 SREBP-1c sterol regulatory element binding protein 1C

WISP2 inducible-signaling pathway protein 2

TAGs triacylglycerolsTNF-α tumor necrosis factor-α TonEBP tonicity-responsive enhancer-binding protein

MUFAs monounsaturated fatty acids

*Mediators of Impaired Adipogenesis in Obesity-Associated Insulin Resistance and T2DM DOI: http://dx.doi.org/10.5772/intechopen.88746*


*Adipose Tissue - An Update*

**Competing interests**

**Authors' contributions**

COX-2 cyclooxygenase-2

4-HNE 4-hydroxynonenal

AA arachidonic acid

DAGs diacylglycerols

15-d-PGJ2 15-deoxy-Δ12,14-prostaglandin J2

DBC1 deleted in bladder cancer protein 1

EPO nonerythropoietic derived peptide

GIP glucose-dependent insulinotropic polypeptide

IKKβ inhibitor of nuclear factor kappa-B kinase subunit β

8-OHdG 8-hydroxy-2-deoxyguanosine

ATGL adipose triglyceride lipase BMP4 bone morphogenetic protein 4 C/EBP CCAAT/enhancer-binding protein

CAD Coronary artery disease cdk5 cyclin-dependent kinase 5

DHA docosahexaenoic acid DMEM dexamethasone DMSO dimethyl sulfoxide EETs epoxyeicosatrienoic acids EPA eicosapentaenoic acid

ER endoplasmic reticulum FABP4 fatty acid-binding protein 4

HSL hormone-sensitive lipase

MCFAs medium chain fatty acids

MCPIP Mcp-1-induced protein

MCP-1 monocyte chemoattractant protein-1

IFN-γ interferon-γ

IL-6 interleukin 6 IR insulin resistance IS insulin sensitive LA linoleic acid LPL lipoprotein lipase LXR liver X receptors

**Abbreviations**

important role in adipogenesis as various fatty acid species such as PUFAs, MUFAs, and MCFAs were shown to regulate preadipocyte differentiation at various degrees depending on their composition. Finally, various environmental factors were suggested to impact adipogenesis, mainly through triggering inflammation and oxidative stress, leading to impairment of adipogenesis and increased risk of IR.

All authors participated in reviewing the literature and preparing and approving

the manuscript. MAE is responsible for the integrity of the work as a whole.

The authors declare that they have no competing interests.

**110**

*Adipose Tissue - An Update*

### **Author details**

Haya Al-Sulaiti1 , Alexander S. Dömling1 and Mohamed A. Elrayess2 \*

1 Department of Drug Design, University of Groningen, Groningen, Netherlands

2 Biomedical Research Center (BRC), Qatar University, Doha, Qatar

\*Address all correspondence to: maelrayess@hotmail.com

© 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.

**113**

*Mediators of Impaired Adipogenesis in Obesity-Associated Insulin Resistance and T2DM*

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**Author details**

Haya Al-Sulaiti1

, Alexander S. Dömling1

\*Address all correspondence to: maelrayess@hotmail.com

provided the original work is properly cited.

1 Department of Drug Design, University of Groningen, Groningen, Netherlands

© 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 Biomedical Research Center (BRC), Qatar University, Doha, Qatar

and Mohamed A. Elrayess2

\*

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in modest obesity and early metabolic dysfunction. PLoS One.

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1146-1156

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2017;**12**(2):e0170728

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2015;**6**:401-408

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2004;**114**(12):1752-1761

2010;**44**(10):1098-1124

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of adipose precursor cells. The

and Therapy. 2013;**4**(2):28

2018;**22**(2):786-796

Journal of Clinical Endocrinology and Metabolism. 2016;**101**(12):4974-4983

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2012;**113**(6):1926-1935

[89] Okuno Y et al. Oxidative stress inhibits healthy adipose expansion through suppression of SREBF1 mediated lipogenic pathway. Diabetes.

[90] Tchkonia T et al. Fat tissue, aging, and cellular senescence. Aging Cell.

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[94] Higdon A et al. Cell signalling by reactive lipid species: New

The Biochemical Journal. 2012;**442**(3):453-464

concepts and molecular mechanisms.

[95] Bauer G, Zarkovic N. Revealing mechanisms of selective, concentrationdependent potentials of 4-hydroxy-2 nonenal to induce apoptosis in cancer cells through inactivation of membraneassociated catalase. Free Radical Biology

and Medicine. 2015;**81**:128-144

Life. 2006;**58**(5-6):372-373

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[106] Castro JP, Grune T, Speckmann B. The two faces of reactive oxygen species (ROS) in adipocyte function and dysfunction. Biological Chemistry. 2016;**397**(8):709-724

[107] Alcala M et al. Short-term vitamin E treatment impairs reactive oxygen species signaling required for adipose tissue expansion, resulting in fatty liver and insulin resistance in obese mice. PLoS One. 2017;**12**(10):e0186579

[108] Pieralisi A et al. N-acetylcysteine inhibits lipid accumulation in mouse embryonic adipocytes. Redox Biology. 2016;**9**:39-44

[109] Peris E et al. Antioxidant treatment induces reductive stress associated with mitochondrial dysfunction in adipocytes. The Journal of Biological Chemistry. 2019;**294**(7):2340-2352

[110] Findeisen HM et al. Oxidative stress accumulates in adipose tissue during aging and inhibits adipogenesis. PLoS One. 2011;**6**(4):e18532

[111] Zhang C, Klett EL, Coleman RA. Lipid signals and insulin resistance. Journal of Clinical Lipidology. 2013;**8**(6):659-667

[112] Jiao P et al. FFA-induced adipocyte inflammation and insulin resistance: Involvement of ER stress and IKKbeta pathways. Obesity (Silver Spring). 2011;**19**(3):483-491

[113] Furuhashi M, Hotamisligil GS. Fatty acid-binding proteins: Role in metabolic diseases and potential as

drug targets. Nature Reviews. Drug Discovery. 2008;**7**(6):489-503

[114] Summers SA. Ceramides in insulin resistance and lipotoxicity. Progress in Lipid Research. 2006;**45**(1):42-72

[115] Barbarroja N et al. Increased dihydroceramide/ceramide ratio mediated by defective expression of degs1 impairs adipocyte differentiation and function. Diabetes. 2015;**64**(4):1180-1192

[116] Papackova Z, Cahova M. Fatty acid signaling: The new function of intracellular lipases. International Journal of Molecular Sciences. 2015;**16**(2):3831-3855

[117] Roy D et al. Coordinated transcriptional control of adipocyte triglyceride lipase (Atgl) by transcription factors Sp1 and peroxisome proliferator-activated receptor γ (PPARγ) during adipocyte differentiation. The Journal of Biological Chemistry. 2017;**292**(36):14827-14835

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[119] Clarke SD. The multi-dimensional regulation of gene expression by fatty acids: Polyunsaturated fats as nutrient sensors. Current Opinion in Lipidology. 2004;**15**(1):13-18

[120] Kersten S. Effects of fatty acids on gene expression: Role of peroxisome proliferator-activated receptor alpha, liver X receptor alpha and sterol regulatory element-binding protein-1c. The Proceedings of the Nutrition Society. 2002;**61**(3):371-374

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[124] Yu K et al. Differential

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1993;**90**(6):2160-2164

2004;**23**(2):139-151

2003;**92**(4):308-316

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polyunsaturated fatty acids and colon cancer prevention. Clinical Nutrition.

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[140] Nakamura MT et al. Mechanisms of regulation of gene expression by fatty acids. Lipids. 2004;**39**(11):1077-1083

[141] Cho K-J et al. Alpha-lipoic acid inhibits adipocyte differentiation by regulating pro-adipogenic transcription factors via mitogenactivated protein kinase pathways. The Journal of Biological Chemistry. 2003;**278**(37):34823-34833

[142] Goto T et al. 10-oxo-12(Z) octadecenoic acid, a linoleic acid metabolite produced by gut lactic acid bacteria, potently activates PPARγ and stimulates adipogenesis. Biochemical and Biophysical Research Communications. 2015;**459**(4):597-603

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[144] Ren B et al. Polyunsaturated fatty acid suppression of hepatic fatty acid synthase and S14 gene expression does not require peroxisome proliferator-activated receptor alpha.

The Journal of Biological Chemistry. 1997;**272**(43):26827-26832

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[146] Takeuchi H et al. Comparative effects of dietary fat types on hepatic enzyme activities related to the synthesis and oxidation of fatty acid and to lipogenesis in rats. Bioscience, Biotechnology, and Biochemistry. 2001;**65**(8):1748-1754

[147] Madsen L, Petersen RK, Kristiansen K. Regulation of adipocyte differentiation and function by polyunsaturated fatty acids. Biochimica et Biophysica Acta. 2005;**1740**(2):266-286

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[172] Tsuboi H et al. Prostanoid EP4 receptor is involved in suppression of 3T3-L1 adipocyte differentiation. Biochemical and Biophysical Research Communications. 2004;**322**(3):1066-1072

[173] Li R et al. CYP2J2 attenuates metabolic dysfunction in diabetic mice by reducing hepatic inflammation via the PPARγ. American Journal of Physiology. Endocrinology and Metabolism. 2015;**308**(4):E270-E282

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Physiology-Endocrinology and Metabolism. 2002;**282**(6):E1352-E1359

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[177] Cha SH et al. Chronic docosahexaenoic acid intake enhances expression of the gene for uncoupling protein 3 and affects pleiotropic mRNA levels in skeletal muscle of aged C57BL/6NJcl mice. The Journal of Nutrition. 2001;**131**(10):2636-2642

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[181] Nakatani T et al. A low fish oil inhibits SREBP-1 proteolytic cascade, while a high-fish-oil feeding decreases SREBP-1 mRNA in mice liver: Relationship to anti-obesity. Journal of Lipid Research. 2003;**44**(2):369-379

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Oleo Science. 2019

2005;**336**(3):909-917

1994;**35**(5):930-937

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Grimaldi PA. Fatty acids as signal transducing molecules: Involvement in the differentiation of preadipose to adipose cells. Journal of Lipid Research.

[188] Davies JD et al. Adipocytic differentiation and liver x receptor pathways regulate the accumulation

[189] Ding S, Mersmann HJ. Fatty acids modulate porcine adipocyte differentiation and transcripts for transcription factors and adipocytecharacteristic proteins\*. The Journal

of Nutritional Biochemistry.

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2001;**12**(2):101-108

2003;**14**(5):266-274

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2005;**280**(19):19146-19155

2014;**40**(1):1-14

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[194] Bartlett DE et al. Uremic toxins activates Na/K-ATPase oxidant

amplification loop causing phenotypic changes in adipocytes in In vitro models. International Journal of Molecular

Sciences. 2018;**19**(9):2685

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[184] Liberato MV et al. Medium chain fatty acids are selective peroxisome proliferator activated receptor (PPAR) γ activators and pan-PPAR partial agonists. PLoS One. 2012;**7**(5):e36297

[185] Senarath S et al. Comparison of the effects of long-chain monounsaturated fatty acid positional isomers on lipid metabolism in 3T3-L1 cells. Journal of

[186] Zhao G et al. Anti-inflammatory effects of polyunsaturated fatty acids in THP-1 cells. Biochemical and Biophysical Research Communications.

**124**

### *Edited by Leszek Szablewski*

Adipose tissue, a kind of connective tissue, plays different and significant roles in the human body. Its function includes protection against environmental factors, storage of lipids and triacylglycerol, and the process of thermogenesis. It is also involved in the secretion of highly active biomolecules such as steroid hormones, prostaglandins, as well as proteins called "adipokines." On the other hand, disturbances in functions of adipose tissue may cause several pathologies such as obesity and insulin resistance. Obesity is a worldwide health problem, whereas diabetes mellitus due to insulin resistance is defined by the World Health Organization as "a progressive worldwide epidemic." Especially dangerous is visceral accumulation of adipose tissue.This book describes a series of up-to-date topics about physiological and pathological processes in adipose tissue.

Published in London, UK © 2019 IntechOpen © xrender / iStock

Adipose Tissue - An Update

IntechOpen Book Series

Physiology, Volume 4

Adipose Tissue

An Update

*Edited by Leszek Szablewski*