**2. Healthy adipose tissue**

#### **2.1 Morphology and cellular biology**

Adipose tissue (AT) is a type of specialized connective tissue, and as such, it consists of two main components: a cellular population and a specialized extracellular matrix (ECM) [1].

The cellular population is integrated not only by adipocytes (the main cell type, by which receives its name) but also by preadipocytes, mesenchymal stem cells (MSCs), fibroblasts, endothelial and smooth muscle cells of blood vessels and any immune system cell, and adipose tissue macrophages (ATMs) with relevance [2, 3].

Its ECM, as any other, is composed of a wide type of collagens (fibrillar (I and III) and nonfibrillar (IV, VI, and VIII)), laminins, fibronectin, and proteoglycans; especially the external membrane contains a large complex of collagen IV and VIII as well as heparan sulfate proteoglycans and laminins [4]. AT ECM possesses the highest collagen VI concentration compared to any other body tissue [5, 6]. Altogether, the ECM and the non-adipocyte cellular population receive the name of stromal-vascular fraction (SVF) [7].

#### *2.1.1 Classification*

Histologically, AT is classified according to adipocyte microscopic characteristics as white (WAT), brown (BAT), and beige. White adipocytes are big oval cells with a single lipid droplet that fills the whole cytoplasm, displacing the nucleus and other organelles through periphery; its main function is the storage of energy in the form of triglycerides (TG) and lipolysis. Brown adipocytes are oval cells with multilocular lipid droplets uniformly distributed over the cytoplasm and have a high number of mitochondria, each one with several cristae expressing uncoupling protein 1 (UCP-1), characteristics that reflect an important thermogenic property. Beige adipocytes are cells with brown phenotype within WAT, that is why they are also called brite (brown-in-white) adipocytes; under basal conditions they express low quantity of UCP-1 but can overexpress it upon β-adrenergic simulation and thus acquire thermogenic function [8–10].

Moreover, adipose tissue has an important endocrine function, as it is capable to secrete own specific hormones called adipokines [11].

#### *2.1.2 Fat depots*

In humans WAT constitutes close to 5–10% of total human body weight and is located in two main compartments: intra-abdominal, named visceral AT (VAT), and subcutaneous AT (SCAT), also called hypodermis. VAT coats internal organs and protects them from mechanical friction and damage and can be divided into omental, mesenteric, retroperitoneal, gonadal and pericardial; SCAT is designated according to its superficial or deep situation regarding to the fascia superficialis as lamellar or areolar [12]. Moreover, abdominal and gluteofemoral regions are more relevant regarding of functional properties [13, 14].

**11**

*Adipose Tissue in Health and Disease*

and insulin resistance (IR) [20].

**2.2 Immunometabolism**

in this field.

*2.2.1 Immune response*

metabolic disturbances [23].

leucocyte population [24, 25].

M2 macrophages and its interaction with adipocytes.

remodeling of the extracellular matrix [8].

*DOI: http://dx.doi.org/10.5772/intechopen.90559*

It is remarkable to note that gender-related differences in distribution and quantity exist. While women have more SCAT (especially in gluteofemoral and peripheral regions), men have more VAT because SCAT has higher levels of estrogen

In rodents, the main SCAT pads are anterior, from the neck to the axillae running through the interscapular area, and posterior, from the dorsolumbar to the gluteal region running through the inguinal region. Also, the striated muscle called *panniculus carnosus* clearly separates two layers of WAT depots: one directly underlying the reticular dermis and SCAT as such [17]; the former compartment is designated as dermal WAT (DWAT), composed primarily by intradermal adipocytes*.* These two terms were proposed as a redefinition of the nomenclature of skin-associated adipocytes, as it more accurately reflects their immediate developmental origin and anatomical location; humans, although not having a *panniculus carnosus*, possess functional and morphological distinctions between DWAT and SCAT [18, 19].

Differentiation, lipolytic and endocrine activity, and leucocyte population differ between VAT and SCAT, conferring them distinct metabolic properties and, in case of VAT, attribution of metabolic disturbances like dyslipidemia, glucose intolerance,

As an interdisciplinary field, immunometabolism emerged from discoveries of interdependent functions and mechanisms between the immune system and parenchymal cells of metabolic organs, which confer adaptive processes in homeostasis or disease at cellular, tissue, and systemic level [21, 22]. AT is the most studied

Immune system has an important role on the control of AT homeostatic state, where its main functions are keeping an anti-inflammatory environment and

Under physiologic state, AT leucocyte population is integrated by eosinophils, mast cells, group 2 innate lymphoid cells (ILC2), invariant natural killer T cells (iNKT), regulatory T lymphocytes (Treg), and, of particular interest, adipose tissue macrophages (ATMs). It is proposed that these immune cells contribute to the maintenance of AT integrity through secretion of cytokines such as IL-4, IL-5, IL-13, and IL-10 (a Th2-type immune response) and that under hypercaloric state, macrophage accumulation may be a protective mechanism of the body to cope

IL-33 produced by endothelial stromal cells has a key role in homeostatic maintenance and function of ECM. It is ligand of ST2 receptor, which is expressed in mast cells, Treg, eosinophils, ILC2s, and iNKT cells, practically the whole resident

In vitro and in vivo studies have demonstrated important effects of IL-33: production of IL-5 and IL-13 by Th2 lymphocytes and macrophages, eosinophil IL-4 production and survival, as well as ILC2s survival and expansion, the latter similar for Tregs [26]. iNKT cells express the transcriptional factor E4BP4; in adipose tissue produce anti-inflammatory cytokines, such as IL-2, IL-4, and IL-10; and participate in control of the homeostasis of Treg cells and macrophages in this tissue [27]. IL-25 promotes lipid metabolism and energy production, improves mitochondrial respiratory capacity, and alleviates lipid accumulation in the liver and AT via

and progesterone receptors, while VAT has more androgen receptors [15, 16].

#### *Adipose Tissue in Health and Disease DOI: http://dx.doi.org/10.5772/intechopen.90559*

*Obesity*

cause disease.

**2. Healthy adipose tissue**

lular matrix (ECM) [1].

*2.1.1 Classification*

*2.1.2 Fat depots*

**2.1 Morphology and cellular biology**

stromal-vascular fraction (SVF) [7].

thus acquire thermogenic function [8–10].

secrete own specific hormones called adipokines [11].

relevant regarding of functional properties [13, 14].

role of the immunometabolism in obesity. That containing significant new findings in the field, presenting the state of the art findings, will offer the new insights into interplay in the regulation of inflammation, especially in the tools of the comorbidity, in order to know their mechanisms by metabolic and immune response that

Adipose tissue (AT) is a type of specialized connective tissue, and as such, it consists of two main components: a cellular population and a specialized extracel-

The cellular population is integrated not only by adipocytes (the main cell type, by which receives its name) but also by preadipocytes, mesenchymal stem cells (MSCs), fibroblasts, endothelial and smooth muscle cells of blood vessels and any immune system cell, and adipose tissue macrophages (ATMs) with relevance [2, 3]. Its ECM, as any other, is composed of a wide type of collagens (fibrillar (I and III) and nonfibrillar (IV, VI, and VIII)), laminins, fibronectin, and proteoglycans; especially the external membrane contains a large complex of collagen IV and VIII as well as heparan sulfate proteoglycans and laminins [4]. AT ECM possesses the highest collagen VI concentration compared to any other body tissue [5, 6]. Altogether, the ECM and the non-adipocyte cellular population receive the name of

Histologically, AT is classified according to adipocyte microscopic characteristics as white (WAT), brown (BAT), and beige. White adipocytes are big oval cells with a single lipid droplet that fills the whole cytoplasm, displacing the nucleus and other organelles through periphery; its main function is the storage of energy in the form of triglycerides (TG) and lipolysis. Brown adipocytes are oval cells with multilocular lipid droplets uniformly distributed over the cytoplasm and have a high number of mitochondria, each one with several cristae expressing uncoupling protein 1 (UCP-1), characteristics that reflect an important thermogenic property. Beige adipocytes are cells with brown phenotype within WAT, that is why they are also called brite (brown-in-white) adipocytes; under basal conditions they express low quantity of UCP-1 but can overexpress it upon β-adrenergic simulation and

Moreover, adipose tissue has an important endocrine function, as it is capable to

In humans WAT constitutes close to 5–10% of total human body weight and is located in two main compartments: intra-abdominal, named visceral AT (VAT), and subcutaneous AT (SCAT), also called hypodermis. VAT coats internal organs and protects them from mechanical friction and damage and can be divided into omental, mesenteric, retroperitoneal, gonadal and pericardial; SCAT is designated according to its superficial or deep situation regarding to the fascia superficialis as lamellar or areolar [12]. Moreover, abdominal and gluteofemoral regions are more

**10**

It is remarkable to note that gender-related differences in distribution and quantity exist. While women have more SCAT (especially in gluteofemoral and peripheral regions), men have more VAT because SCAT has higher levels of estrogen and progesterone receptors, while VAT has more androgen receptors [15, 16].

In rodents, the main SCAT pads are anterior, from the neck to the axillae running through the interscapular area, and posterior, from the dorsolumbar to the gluteal region running through the inguinal region. Also, the striated muscle called *panniculus carnosus* clearly separates two layers of WAT depots: one directly underlying the reticular dermis and SCAT as such [17]; the former compartment is designated as dermal WAT (DWAT), composed primarily by intradermal adipocytes*.* These two terms were proposed as a redefinition of the nomenclature of skin-associated adipocytes, as it more accurately reflects their immediate developmental origin and anatomical location; humans, although not having a *panniculus carnosus*, possess functional and morphological distinctions between DWAT and SCAT [18, 19].

Differentiation, lipolytic and endocrine activity, and leucocyte population differ between VAT and SCAT, conferring them distinct metabolic properties and, in case of VAT, attribution of metabolic disturbances like dyslipidemia, glucose intolerance, and insulin resistance (IR) [20].

#### **2.2 Immunometabolism**

As an interdisciplinary field, immunometabolism emerged from discoveries of interdependent functions and mechanisms between the immune system and parenchymal cells of metabolic organs, which confer adaptive processes in homeostasis or disease at cellular, tissue, and systemic level [21, 22]. AT is the most studied in this field.

#### *2.2.1 Immune response*

Immune system has an important role on the control of AT homeostatic state, where its main functions are keeping an anti-inflammatory environment and remodeling of the extracellular matrix [8].

Under physiologic state, AT leucocyte population is integrated by eosinophils, mast cells, group 2 innate lymphoid cells (ILC2), invariant natural killer T cells (iNKT), regulatory T lymphocytes (Treg), and, of particular interest, adipose tissue macrophages (ATMs). It is proposed that these immune cells contribute to the maintenance of AT integrity through secretion of cytokines such as IL-4, IL-5, IL-13, and IL-10 (a Th2-type immune response) and that under hypercaloric state, macrophage accumulation may be a protective mechanism of the body to cope metabolic disturbances [23].

IL-33 produced by endothelial stromal cells has a key role in homeostatic maintenance and function of ECM. It is ligand of ST2 receptor, which is expressed in mast cells, Treg, eosinophils, ILC2s, and iNKT cells, practically the whole resident leucocyte population [24, 25].

In vitro and in vivo studies have demonstrated important effects of IL-33: production of IL-5 and IL-13 by Th2 lymphocytes and macrophages, eosinophil IL-4 production and survival, as well as ILC2s survival and expansion, the latter similar for Tregs [26]. iNKT cells express the transcriptional factor E4BP4; in adipose tissue produce anti-inflammatory cytokines, such as IL-2, IL-4, and IL-10; and participate in control of the homeostasis of Treg cells and macrophages in this tissue [27].

IL-25 promotes lipid metabolism and energy production, improves mitochondrial respiratory capacity, and alleviates lipid accumulation in the liver and AT via M2 macrophages and its interaction with adipocytes.

As we can observe, AT leucocytes produce the Th2-type cytokines, profile that favors the maintenance of ATMs in an anti-inflammatory M2 phenotype, known for the expression of arginase-1 (Arg-1, which inhibits iNOS activity) and production of IL-10 and IL-1Ra. ATMs also play an important lipid "buffering" activity, as they engulf free fatty acids (FFA) coming from adipocytes that have surpassed their lipid storage capacity and unchain lipolysis. Moreover, ATMs engulf death adipocytes that have reached a critical death size (CDS) [28] by a process named efferocytosis [29].

Thus, ATM is the fundamental leucocyte for correct AT functionality, as it engulfs apoptotic cell debris, and, FFA released whether by lipolysis or adipocyte death, promotes ECM reconstruction [30] and provides ECM components as scaffolds for its remodeling in the same way as under wound healing process; all these mechanisms promote adipogenesis and hyperplastic AT expansion. It is worth noting that these beneficial functions take place only under an anti-inflammatory M2 phenotype (**Figure 1**).

#### *2.2.2 ECM remodeling*

The ECM of any specialized connective tissue is essential not only for mechanic and structural sustain but also for providing a network that permits inter- and extracellular communication that enables proper growth and differentiation [1]. AT ECM is no exception, and its remodeling is regulated by resident leucocytes and own adipocytes.

WAT can undergo remodeling in response to changes in energy balance, like ECM degradation by members of the matrix metalloproteinase (MMP) family during adipocyte enlargement (hypertrophy) and allowing expansion by adipogenesis, under a positive energy balance [31, 32]; on the other hand, MMP activity counterregulation is mediated by their tissue inhibitors (TIMPs). The balance between MMPs and TIMPs is critical for ECM integrity and function, and alterations in this proteolysis balance may contribute to many pathological states [33].

Secreted protein, acidic, and rich in cysteine complex (SPARC)/osteonectin and its C and N isoforms contribute to AT ECM remodeling; they modulate cell-ECM contact, cell-cell interaction, ECM deposition, and adipose stem cells (ASCs) migration and posterior incorporation into expanding neovasculature

**13**

*PPARG* [45].

*Adipose Tissue in Health and Disease*

*oxidase*, and *Timp1* [38].

metabolic profile [42].

*DOI: http://dx.doi.org/10.5772/intechopen.90559*

accompanying WAT growth [34]. A study showed that serum concentrations of SPARC and MMP-2 after bariatric surgery decreased, SMAC correlated with HOMA-IR, and MMP-9 inversely correlated with serum adiponectin levels [35]. Regarding vasculature, AT ECM remodeling is influenced by a variety of angiogenic molecules, and it is triggered by transient hypoxia as a result of enlarged adipocytes under a positive energy balance. Hypoxia stimulates the production of angiogenic factors to compensate low perfusion rate; vascular endothelial growth factor (VEGF) is known as a master regulator of angiogenesis and plays crucial roles in the neovascular development of AT with obesity [36]. Hypoxia-inducible factor-1α (HIF-1α) binds to the proximal hypoxia response element in the *VEGF* gene promoter [37]; nevertheless, it also has a role in regulation of ECM remodeling, as overexpression of a constitutively active form of HIF-1α in adipose tissue forced the expression of pro-fibrotic genes, including *Col I* and *III*, *elastin*, *lysyl* 

This shows that detrimental ECM component deposition occurs under chronic hypoxic conditions. Transforming growth factor beta (TGFβ) and tumor necrosis factor-α (TNF-α) are released under acute hypoxia state and act as proangiogenic factors [39, 40], and the latter activates expression of preadipocyte genes in 3T3-L1 adipocytes [41]. This is in contrast to the belief that AT inflammation exerts a fundamentally negative impact on metabolism, postulating the concept "healthy inflammation" under overnutrition, requiring an acute local inflammation in order to prevent lipotoxicity and ectopic lipid accumulation; in this regard, a report showed the analysis of three animal models with constitutive or inducible expression of anti-inflammatory factors and revealed their inability to expand AT, leading to ectopic lipid deposition and deteriorated

Platelet-derived growing factor B (PDGF-B), usually produced by endothelial cells, activates an intracellular signaling cascade binding to its receptor (PDGFRβ) and promotes pericyte detachment and migration around new-forming vessels for maturation, playing key roles in vascular development and wound healing in adults via angiogenic actions [43]. Surprisingly, Onogi Y. and colleagues found that M1 macrophages were a major type of cells expressing PDGF-B in obese adipose tissue and correlated with elevated pericyte detachment in a dose-dependent manner; in contrast, inducible knockout *pdgfrb* mice presented reduced M1 macrophages and CLS formation but increased M2 macrophages. Additionally, they were protected from body weight gain, accumulation of SCAT, VAT, and ectopic fat in muscle and liver and showed improved whole-body glucose metabolism under high-fat diet (HFD) condition. The expression of hypoxic and proinflammatory factors (*Hif1a, Emr1, Itgax, Mrc1, Tnfa, and Ccl2*) was significantly increased by HFD feeding mice, whereas the increasing effects were attenuated in HFD-fed *PDGFRB-*KO mice [44]. Also, increased adipogenic capacity of PDGFRβ+ precursors through *PPARG* overexpression in pericytes resulted in healthy VAT expansion in obesity and adiponectindependent improvements in glucose homeostasis, in contrast with knockout *PPARG* counterparts; moreover, the ability of the thiazolidinedione (TZD) class of antidiabetic drugs to promote healthy visceral WAT remodeling is dependent on mural cell

An experimental in vivo study consisting of brown adipogenesis by β3-adrenergic receptor (ADRB3) activation caused crown-like structures (CLSs) formation: white adipocyte death recruited M2-polarized macrophages with high expression of osteopontin (OPN), which in turn attracted a subpopulation of PDGFRα+ CD44+ (OPN receptor) progenitors that underwent adipogenesis, in contrast with knockout OPN [46]. It is important to highlight that recruited M2 macrophages also showed upregulation of *Arg1* and *Il10* without significant changes

**Figure 1.** *Adipose tissue homeostatic immunometabolism.*

#### *Adipose Tissue in Health and Disease DOI: http://dx.doi.org/10.5772/intechopen.90559*

*Obesity*

efferocytosis [29].

M2 phenotype (**Figure 1**).

*2.2.2 ECM remodeling*

own adipocytes.

As we can observe, AT leucocytes produce the Th2-type cytokines, profile that favors the maintenance of ATMs in an anti-inflammatory M2 phenotype, known for the expression of arginase-1 (Arg-1, which inhibits iNOS activity) and production of IL-10 and IL-1Ra. ATMs also play an important lipid "buffering" activity, as they engulf free fatty acids (FFA) coming from adipocytes that have surpassed their lipid storage capacity and unchain lipolysis. Moreover, ATMs engulf death adipocytes that have reached a critical death size (CDS) [28] by a process named

Thus, ATM is the fundamental leucocyte for correct AT functionality, as it engulfs apoptotic cell debris, and, FFA released whether by lipolysis or adipocyte death, promotes ECM reconstruction [30] and provides ECM components as scaffolds for its remodeling in the same way as under wound healing process; all these mechanisms promote adipogenesis and hyperplastic AT expansion. It is worth noting that these beneficial functions take place only under an anti-inflammatory

The ECM of any specialized connective tissue is essential not only for mechanic

and structural sustain but also for providing a network that permits inter- and extracellular communication that enables proper growth and differentiation [1]. AT ECM is no exception, and its remodeling is regulated by resident leucocytes and

WAT can undergo remodeling in response to changes in energy balance, like ECM degradation by members of the matrix metalloproteinase (MMP) family during adipocyte enlargement (hypertrophy) and allowing expansion by adipogenesis, under a positive energy balance [31, 32]; on the other hand, MMP activity counterregulation is mediated by their tissue inhibitors (TIMPs). The balance between MMPs and TIMPs is critical for ECM integrity and function, and alterations in this

Secreted protein, acidic, and rich in cysteine complex (SPARC)/osteonectin and its C and N isoforms contribute to AT ECM remodeling; they modulate cell-ECM contact, cell-cell interaction, ECM deposition, and adipose stem cells (ASCs) migration and posterior incorporation into expanding neovasculature

proteolysis balance may contribute to many pathological states [33].

**12**

**Figure 1.**

*Adipose tissue homeostatic immunometabolism.*

accompanying WAT growth [34]. A study showed that serum concentrations of SPARC and MMP-2 after bariatric surgery decreased, SMAC correlated with HOMA-IR, and MMP-9 inversely correlated with serum adiponectin levels [35].

Regarding vasculature, AT ECM remodeling is influenced by a variety of angiogenic molecules, and it is triggered by transient hypoxia as a result of enlarged adipocytes under a positive energy balance. Hypoxia stimulates the production of angiogenic factors to compensate low perfusion rate; vascular endothelial growth factor (VEGF) is known as a master regulator of angiogenesis and plays crucial roles in the neovascular development of AT with obesity [36]. Hypoxia-inducible factor-1α (HIF-1α) binds to the proximal hypoxia response element in the *VEGF* gene promoter [37]; nevertheless, it also has a role in regulation of ECM remodeling, as overexpression of a constitutively active form of HIF-1α in adipose tissue forced the expression of pro-fibrotic genes, including *Col I* and *III*, *elastin*, *lysyl oxidase*, and *Timp1* [38].

This shows that detrimental ECM component deposition occurs under chronic hypoxic conditions. Transforming growth factor beta (TGFβ) and tumor necrosis factor-α (TNF-α) are released under acute hypoxia state and act as proangiogenic factors [39, 40], and the latter activates expression of preadipocyte genes in 3T3-L1 adipocytes [41]. This is in contrast to the belief that AT inflammation exerts a fundamentally negative impact on metabolism, postulating the concept "healthy inflammation" under overnutrition, requiring an acute local inflammation in order to prevent lipotoxicity and ectopic lipid accumulation; in this regard, a report showed the analysis of three animal models with constitutive or inducible expression of anti-inflammatory factors and revealed their inability to expand AT, leading to ectopic lipid deposition and deteriorated metabolic profile [42].

Platelet-derived growing factor B (PDGF-B), usually produced by endothelial cells, activates an intracellular signaling cascade binding to its receptor (PDGFRβ) and promotes pericyte detachment and migration around new-forming vessels for maturation, playing key roles in vascular development and wound healing in adults via angiogenic actions [43]. Surprisingly, Onogi Y. and colleagues found that M1 macrophages were a major type of cells expressing PDGF-B in obese adipose tissue and correlated with elevated pericyte detachment in a dose-dependent manner; in contrast, inducible knockout *pdgfrb* mice presented reduced M1 macrophages and CLS formation but increased M2 macrophages. Additionally, they were protected from body weight gain, accumulation of SCAT, VAT, and ectopic fat in muscle and liver and showed improved whole-body glucose metabolism under high-fat diet (HFD) condition. The expression of hypoxic and proinflammatory factors (*Hif1a, Emr1, Itgax, Mrc1, Tnfa, and Ccl2*) was significantly increased by HFD feeding mice, whereas the increasing effects were attenuated in HFD-fed *PDGFRB-*KO mice [44]. Also, increased adipogenic capacity of PDGFRβ+ precursors through *PPARG* overexpression in pericytes resulted in healthy VAT expansion in obesity and adiponectindependent improvements in glucose homeostasis, in contrast with knockout *PPARG* counterparts; moreover, the ability of the thiazolidinedione (TZD) class of antidiabetic drugs to promote healthy visceral WAT remodeling is dependent on mural cell *PPARG* [45].

An experimental in vivo study consisting of brown adipogenesis by β3-adrenergic receptor (ADRB3) activation caused crown-like structures (CLSs) formation: white adipocyte death recruited M2-polarized macrophages with high expression of osteopontin (OPN), which in turn attracted a subpopulation of PDGFRα+ CD44+ (OPN receptor) progenitors that underwent adipogenesis, in contrast with knockout OPN [46]. It is important to highlight that recruited M2 macrophages also showed upregulation of *Arg1* and *Il10* without significant changes in proinflammatory markers, indicating that ADRB3-mediated adipogenesis involves recruitment of macrophages that mediate non-inflammatory tissue repair [47]. Another study combining experiments in mouse models and human conditions reported that PDGFRα + CD9high cells originate pro-fibrotic cells, while their CD9low counterparts harbored pro-adipogenic potential; frequency of PDGFRα + CD9high in omental WAT (oWAT) correlated not only to oWAT fibrosis level but also to the severity of insulin resistance and T2D [48].

Adipokines can also help regulate angiogenesis, a sustained and progressive increase in leptin resulting from hypoxic conditions could induce VEGF and receptor (VEGFR2) expression, activate sirtuin 1 (SIRT1), and subsequent HIF-2α stabilization promoting its activity [49]*.*

#### *2.2.3 Glucose and lipid metabolism*

A steady and continuous energy supply is necessary for all cells' survival; the production of the principal high-energy molecule, the adenosine triphosphate (ATP), is primarily obtained by the metabolism of such molecules as glucose and fatty acids. In the case of carbohydrates, these are the main source of energy in almost every living organism, from archaea to humans. It is not only the supply of these molecules, but also the intricate mechanism of regulation of pathways that control the consumption and storage of these biomolecules.

For example, after a meal, or what is called a post absorptive state, there is an increment of plasmatic glucose concentration which results in the secretion of hormones such as insulin by the pancreas; this contributes to the regulation of glucose metabolism as well, and the physiological response varies on every tissue, as can been seen in muscle and liver, where insulin favors glycolysis and glycogenesis. Nevertheless, this hormone not only alters the carbohydrates metabolism, but also promotes cholesterol synthesis and lipogenesis (or TG synthesis) in hepatic and adipose tissues [50].

In the case of glycolysis, it represents the central path for glucose metabolism and provides multiple intermediate products. On aerobic conditions, it starts in the cytoplasm of the cell, with glucose as a substrate, which is partially oxidized by 10 enzymatic reactions, obtaining two pyruvate molecules, reducing equivalents such as NADH (nicotinamide adenine dinucleotide in reduced form) and a net production of 2 ATPs for each glucose [51].

Afterward, the pyruvate molecules will be transformed into acetyl-CoA and transported into the mitochondria to continue their oxidation in the tricarboxylate cycle to produce two CO2 molecules, three NADH and one FADH (flavin adenine dinucleotide in reduced form). The latter will transfer their electrons to the mitochondrial complexes of the electron respiratory chain; a series of redox transformation and the aid of molecular oxygen will finally converge in the synthesis of ATP by the ATP synthase complex.

Both ATP, NADH, and acetyl-CoA are metabolites that are shown to be thermodynamically favorable and are indicated as the protagonists in cellular energy metabolism [52].

After glycogen, the body stores energy in the form of TG in adipose tissue; nevertheless, diverse types of lipids are required for the maintenance of cellular functions, not only for energetic ones, but also structural (such as phospholipids) or for the formation of specialized products like steroid hormones. These are obtained from diet, absorbed and subsequently transported by lipoproteins such as the very high-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL), all of these ensembled by the liver. FFAs are a major source of acetyl-CoA molecules by β-oxidation, these molecules continue their oxidation in

**15**

*Adipose Tissue in Health and Disease*

*DOI: http://dx.doi.org/10.5772/intechopen.90559*

amount of energy at the cellular level.

**3. Adipose tissue and disease**

context by healthcare professionals.

body weight of individuals [57].

as amplifiers of this process [62].

disease (CVD).

**3.1 Insulin resistance**

*3.1.1 Obesity as a trigger*

the tricarboxylate cycle and the electron respiratory chain, providing a significant

(SREBPs) and hormonal control for an adequate function [53].

been suggested, particularly for miR-122 and miR-33 [54].

Due to the importance of these biomolecules, there is a narrow regulation that includes transcription factors such as sterol regulatory element-binding proteins

Although these regulatory mechanisms are recognized, the possible regulatory activity that miRNAs may have in lipid and cholesterol homeostasis has recently

Obesity is a disease of multifactorial origin with a worldwide increasing prevalence; it entails an injurious health status for individuals, which represents a serious public health issue. This condition is associated to diverse diseases and has a complex treatment, being the reason why it must be assessed in a multidisciplinary

It is defined as an abnormal or excessive fat accumulation that can be detrimental for health [55]. It originates from the interrelation of inadequate food intake and/or overfeeding, sedentary lifestyle, and psychological, genetic, and ambiental factors. The excessive adiposity status hinders the disease reversion because of the difficulty to perform physical activity and the metabolic and satiety dysregulation [56]. Obesity develops a diversity of somatic complications such as respiratory, mechanic, cardiovascular, and metabolic, as well as psychological and social, which make its assessment, prognosis, and intervention even more complicated. Diagnosis is preceded by an anthropometric evaluation, which correlates adiposity with a total

Progressive AT expansion in the organism, given by a positive energy balance from excessive macronutrients and calorie intake, entails an elevated number of circulating FFA that triggers a deregulation in the organism, from changes in body structure to changes at local and systemic levels [58]. This excessive AT induces a chronic inflammatory state, also named lipoinflammation, causing hypoxia of adipocytes [59]. AT hypoxia and inflammation correlate with the risk of developing insulin resistance (IR), type 2 diabetes (T2D), and cardiovascular

When the organism is under positive energy balance, energy excess accumulates in AT, giving place to SCAT hyperplasia until a physiologic allowed limit as energy reservoir is reached. When energy excess prevails, it is now stored at VAT; unfortunately this depot does not possess a great capacity as SCAT, resulting in adipocyte hypertrophy and subsequent android, central, or visceral adiposity [60, 61].

Central obesity is highly associated with T2D and CVD. AT is the pathogenic site where obesity-induced local IR originates before being systemic; its secretory genetic expression profile of endocrine and paracrine bioactive substances reflects a generalized inflammatory local state, the reason why adipocyte is referred to as key to the onset and development of obesity-induced inflammation and to macrophages

As aforementioned, AT initially plays a role in energy reservoir but also has a significant function in metabolism and immune system. Resident ATMs are key in IR onset, as they produce proinflammatory molecules which can explain more than

#### *Adipose Tissue in Health and Disease DOI: http://dx.doi.org/10.5772/intechopen.90559*

the tricarboxylate cycle and the electron respiratory chain, providing a significant amount of energy at the cellular level.

Due to the importance of these biomolecules, there is a narrow regulation that includes transcription factors such as sterol regulatory element-binding proteins (SREBPs) and hormonal control for an adequate function [53].

Although these regulatory mechanisms are recognized, the possible regulatory activity that miRNAs may have in lipid and cholesterol homeostasis has recently been suggested, particularly for miR-122 and miR-33 [54].

## **3. Adipose tissue and disease**

#### **3.1 Insulin resistance**

*Obesity*

in proinflammatory markers, indicating that ADRB3-mediated adipogenesis involves recruitment of macrophages that mediate non-inflammatory tissue repair [47]. Another study combining experiments in mouse models and human conditions reported that PDGFRα + CD9high cells originate pro-fibrotic cells, while their CD9low counterparts harbored pro-adipogenic potential; frequency of PDGFRα + CD9high in omental WAT (oWAT) correlated not only to oWAT fibrosis level but also

Adipokines can also help regulate angiogenesis, a sustained and progressive increase in leptin resulting from hypoxic conditions could induce VEGF and receptor (VEGFR2) expression, activate sirtuin 1 (SIRT1), and subsequent HIF-2α

A steady and continuous energy supply is necessary for all cells' survival; the production of the principal high-energy molecule, the adenosine triphosphate (ATP), is primarily obtained by the metabolism of such molecules as glucose and fatty acids. In the case of carbohydrates, these are the main source of energy in almost every living organism, from archaea to humans. It is not only the supply of these molecules, but also the intricate mechanism of regulation of pathways that

For example, after a meal, or what is called a post absorptive state, there is an increment of plasmatic glucose concentration which results in the secretion of hormones such as insulin by the pancreas; this contributes to the regulation of glucose metabolism as well, and the physiological response varies on every tissue, as can been seen in muscle and liver, where insulin favors glycolysis and glycogenesis. Nevertheless, this hormone not only alters the carbohydrates metabolism, but also promotes cholesterol synthesis and lipogenesis (or TG synthesis) in hepatic and

In the case of glycolysis, it represents the central path for glucose metabolism and provides multiple intermediate products. On aerobic conditions, it starts in the cytoplasm of the cell, with glucose as a substrate, which is partially oxidized by 10 enzymatic reactions, obtaining two pyruvate molecules, reducing equivalents such as NADH (nicotinamide adenine dinucleotide in reduced form) and a net produc-

Afterward, the pyruvate molecules will be transformed into acetyl-CoA and transported into the mitochondria to continue their oxidation in the tricarboxylate cycle to produce two CO2 molecules, three NADH and one FADH (flavin adenine dinucleotide in reduced form). The latter will transfer their electrons to the mitochondrial complexes of the electron respiratory chain; a series of redox transformation and the aid of molecular oxygen will finally converge in the synthesis of ATP by

Both ATP, NADH, and acetyl-CoA are metabolites that are shown to be thermodynamically favorable and are indicated as the protagonists in cellular energy

After glycogen, the body stores energy in the form of TG in adipose tissue; nevertheless, diverse types of lipids are required for the maintenance of cellular functions, not only for energetic ones, but also structural (such as phospholipids) or for the formation of specialized products like steroid hormones. These are obtained from diet, absorbed and subsequently transported by lipoproteins such as the very high-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL), all of these ensembled by the liver. FFAs are a major source of acetyl-CoA molecules by β-oxidation, these molecules continue their oxidation in

to the severity of insulin resistance and T2D [48].

control the consumption and storage of these biomolecules.

stabilization promoting its activity [49]*.*

*2.2.3 Glucose and lipid metabolism*

adipose tissues [50].

tion of 2 ATPs for each glucose [51].

the ATP synthase complex.

metabolism [52].

**14**

#### *3.1.1 Obesity as a trigger*

Obesity is a disease of multifactorial origin with a worldwide increasing prevalence; it entails an injurious health status for individuals, which represents a serious public health issue. This condition is associated to diverse diseases and has a complex treatment, being the reason why it must be assessed in a multidisciplinary context by healthcare professionals.

It is defined as an abnormal or excessive fat accumulation that can be detrimental for health [55]. It originates from the interrelation of inadequate food intake and/or overfeeding, sedentary lifestyle, and psychological, genetic, and ambiental factors. The excessive adiposity status hinders the disease reversion because of the difficulty to perform physical activity and the metabolic and satiety dysregulation [56].

Obesity develops a diversity of somatic complications such as respiratory, mechanic, cardiovascular, and metabolic, as well as psychological and social, which make its assessment, prognosis, and intervention even more complicated. Diagnosis is preceded by an anthropometric evaluation, which correlates adiposity with a total body weight of individuals [57].

Progressive AT expansion in the organism, given by a positive energy balance from excessive macronutrients and calorie intake, entails an elevated number of circulating FFA that triggers a deregulation in the organism, from changes in body structure to changes at local and systemic levels [58]. This excessive AT induces a chronic inflammatory state, also named lipoinflammation, causing hypoxia of adipocytes [59]. AT hypoxia and inflammation correlate with the risk of developing insulin resistance (IR), type 2 diabetes (T2D), and cardiovascular disease (CVD).

When the organism is under positive energy balance, energy excess accumulates in AT, giving place to SCAT hyperplasia until a physiologic allowed limit as energy reservoir is reached. When energy excess prevails, it is now stored at VAT; unfortunately this depot does not possess a great capacity as SCAT, resulting in adipocyte hypertrophy and subsequent android, central, or visceral adiposity [60, 61].

Central obesity is highly associated with T2D and CVD. AT is the pathogenic site where obesity-induced local IR originates before being systemic; its secretory genetic expression profile of endocrine and paracrine bioactive substances reflects a generalized inflammatory local state, the reason why adipocyte is referred to as key to the onset and development of obesity-induced inflammation and to macrophages as amplifiers of this process [62].

As aforementioned, AT initially plays a role in energy reservoir but also has a significant function in metabolism and immune system. Resident ATMs are key in IR onset, as they produce proinflammatory molecules which can explain more than 50% of secretion of TNF-α, by the action of insulin on adipocytes and on peripheric organs of the body [63].

Other implicated adipokines are resistin and IL-6, which stimulate hormonesensitive lipase (HSL) activity resulting in triglycerides cleavage and subsequent glycerol and FFA release; these high circulating FFA levels are the cause and consequence of IR and T2D [64].

We can broadly elucidate that adipocytes and ATMs synthesize proinflammatory molecules and that weight increase at the expense of AT will contribute in turn to the perpetuation of chronic inflammation by increasing the levels of circulating cytokines. Required actions to help reverse the IR process should be focused on establishing a healthy diet accompanied by exercise; these will help to reduce the proinflammatory state, while downregulation of TNF-α and IL-6 expression of adipocytes occur. Meanwhile, exercise by its own will enhance mitochondrial FFA metabolism, avoiding their storage [65].

Other factors involved in IR and inflammation are implicated by diet and related to gut microbiota, which in turn demonstrates how an excessive saturated fat consumption can drive an important bacterial lipopolysaccharide (LPS) production, which impacts on systemic inflammation [58].

Initial steps that launch the inflammatory response are less well elucidated. On experimental studies with HFD-induced obesity murine models, HIF-1α levels are observed before the onset of a significant adiposity status; under this situation, adipocyte hypoxia and HIF-1α act as early triggers of inflammation and IR [59].

#### *3.1.2 Inflammatory pathway*

Adipose tissue complex and diverse functions have implications in the whole body, and cytokines are involved in his physiologic response. In obesity condition the major cytokines expressed by AT are leptin, resistin, TNFα, chemerin, MCP-1 and IL-6 [66, 67]. On the other hand, the adipose cells are both hyperplastic and hypertrophic, and in this state induce the inflammatory process. Dysregulation of adipose tissue promotes incorrect remodeling and subsequent inflammation, according to recruitment of macrophages and expression of chemotactic cytokines like MCP-1, TNFα and chemerin, to mention some of them. The phenotype involved is the M1 pro-inflammatory and evidence shows that this situation is not only local, but also systemic and this promotes further inflammation explaining how obesity can be the etiologic cause of other diseases [68, 69].

In addition, it is well known that this mechanism promotes insulin resistance, which is the previous phase before the development of T2D. However, the adipocyte is in a very close communication with the macrophage making the inflammatory process redundant and more complex. Nevertheless, in lean adipose tissue, it is typically the opposite, meaning that macrophages differentiate into a M2 antiinflammatory phenotype, releasing IL-10, TGFβ, IL-4, and other regulatory cytokines [70]. Otherwise other mechanisms that can promote the anti-inflammatory pathway, like the consumption of Omega 3 fatty acids, exist [71].

Taking it all together, obesity results from genetic, epigenetic, physiological, behavioral, molecular and environmental factors that lead the proinflammatory phenotype [72, 73].

#### *3.1.3 Molecular mechanism*

It is described that adipose cells derive from a stem cell that can differentiate into adipocytes, chondrocytes, osteoblasts, and myocytes [74].

**17**

**Figure 2.**

*Adipose Tissue in Health and Disease*

production of adiponectin [76, 77].

early than PPAR-γ (**Figure 2**) [78].

*3.1.4 Role of adipokines and myokines*

among others [79].

characterization [82].

*DOI: http://dx.doi.org/10.5772/intechopen.90559*

In a first phase, adipoblasts can be addressed to the adipogenic lineage and become preadipocytes. If the stimuli in the tissue continue, these cells maturate to

There are two main transcription factors that are involved in the differentiation of the adipocyte, CCAAT/enhancer-binding protein α (C/EBP-α), and peroxisome proliferator-activated receptor γ (PPAR-γ). PPAR-γ is the most described transcriptional factor, and its expression is regulated by the co-factor PGC1α and the

Transcription factors that belong to the C/EBP family also have a crucial play in the differentiation, and there are reports that this factor can be activating more

The dysfunction in the capacity of generating healthy adipose tissue has several metabolic consequences, like dyslipidemia, hypertension, and insulin resistance

Many molecular mechanisms are involved since the adipocytes have different gene expression patterns, leading to the expression of different types of adipokines depending the phenotype induced in the tissue. Healthy expansion of adipocytes depends on the plasticity of the extracellular matrix, but in obesity there is a limit-

Skeletal muscle compounds 40% of total body weight in healthy individuals. The muscle is the major site for the insulin-stimulated glucose uptake and lipid

Adipose tissue possesses more than 600 potentially secretory proteins, which

Additionally in adipokines there is a cross talk between these and myokines, which are synthetized by the muscle. Nevertheless, both tissues can express the same cytokines creating a regulation process with a strong communication. The most characterized cytokines are chemerin, TNFa, MCP-1 and IL-6. It is demonstrated that WAT deposits exist in skeletal muscle and facilitate communication,

metabolism, so it is an important part of metabolism maintenance [81].

means that more adipokines and myokines are still in line for discovery and

become mature adipose cells with lipid storage capacity [75].

ing in the oxygen diffusion, and it becomes hypoxic [80].

also, these tissues usually are in close anatomical proximity.

*Adipose tissue differentiation and hyperplasia and hypertrophy consequences.*

#### *Adipose Tissue in Health and Disease DOI: http://dx.doi.org/10.5772/intechopen.90559*

*Obesity*

organs of the body [63].

quence of IR and T2D [64].

*3.1.2 Inflammatory pathway*

metabolism, avoiding their storage [65].

which impacts on systemic inflammation [58].

50% of secretion of TNF-α, by the action of insulin on adipocytes and on peripheric

Other implicated adipokines are resistin and IL-6, which stimulate hormonesensitive lipase (HSL) activity resulting in triglycerides cleavage and subsequent glycerol and FFA release; these high circulating FFA levels are the cause and conse-

We can broadly elucidate that adipocytes and ATMs synthesize proinflammatory molecules and that weight increase at the expense of AT will contribute in turn to the perpetuation of chronic inflammation by increasing the levels of circulating cytokines. Required actions to help reverse the IR process should be focused on establishing a healthy diet accompanied by exercise; these will help to reduce the proinflammatory state, while downregulation of TNF-α and IL-6 expression of adipocytes occur. Meanwhile, exercise by its own will enhance mitochondrial FFA

Other factors involved in IR and inflammation are implicated by diet and related to gut microbiota, which in turn demonstrates how an excessive saturated fat consumption can drive an important bacterial lipopolysaccharide (LPS) production,

Initial steps that launch the inflammatory response are less well elucidated. On experimental studies with HFD-induced obesity murine models, HIF-1α levels are observed before the onset of a significant adiposity status; under this situation, adipocyte hypoxia and HIF-1α act as early triggers of inflammation and IR [59].

Adipose tissue complex and diverse functions have implications in the whole body, and cytokines are involved in his physiologic response. In obesity condition the major cytokines expressed by AT are leptin, resistin, TNFα, chemerin, MCP-1 and IL-6 [66, 67]. On the other hand, the adipose cells are both hyperplastic and hypertrophic, and in this state induce the inflammatory process. Dysregulation of adipose tissue promotes incorrect remodeling and subsequent inflammation, according to recruitment of macrophages and expression of chemotactic cytokines like MCP-1, TNFα and chemerin, to mention some of them. The phenotype involved is the M1 pro-inflammatory and evidence shows that this situation is not only local, but also systemic and this promotes further inflammation explaining

In addition, it is well known that this mechanism promotes insulin resistance, which is the previous phase before the development of T2D. However, the adipocyte is in a very close communication with the macrophage making the inflammatory process redundant and more complex. Nevertheless, in lean adipose tissue, it is typically the opposite, meaning that macrophages differentiate into a M2 antiinflammatory phenotype, releasing IL-10, TGFβ, IL-4, and other regulatory cytokines [70]. Otherwise other mechanisms that can promote the anti-inflammatory

Taking it all together, obesity results from genetic, epigenetic, physiological, behavioral, molecular and environmental factors that lead the proinflammatory

It is described that adipose cells derive from a stem cell that can differentiate into

how obesity can be the etiologic cause of other diseases [68, 69].

pathway, like the consumption of Omega 3 fatty acids, exist [71].

adipocytes, chondrocytes, osteoblasts, and myocytes [74].

**16**

phenotype [72, 73].

*3.1.3 Molecular mechanism*

In a first phase, adipoblasts can be addressed to the adipogenic lineage and become preadipocytes. If the stimuli in the tissue continue, these cells maturate to become mature adipose cells with lipid storage capacity [75].

There are two main transcription factors that are involved in the differentiation of the adipocyte, CCAAT/enhancer-binding protein α (C/EBP-α), and peroxisome proliferator-activated receptor γ (PPAR-γ). PPAR-γ is the most described transcriptional factor, and its expression is regulated by the co-factor PGC1α and the production of adiponectin [76, 77].

Transcription factors that belong to the C/EBP family also have a crucial play in the differentiation, and there are reports that this factor can be activating more early than PPAR-γ (**Figure 2**) [78].

The dysfunction in the capacity of generating healthy adipose tissue has several metabolic consequences, like dyslipidemia, hypertension, and insulin resistance among others [79].

Many molecular mechanisms are involved since the adipocytes have different gene expression patterns, leading to the expression of different types of adipokines depending the phenotype induced in the tissue. Healthy expansion of adipocytes depends on the plasticity of the extracellular matrix, but in obesity there is a limiting in the oxygen diffusion, and it becomes hypoxic [80].
