3. AT remodeling in obesity

#### 3.1. Infiltration of immune cells into AT

AT is mainly comprised of adipocytes, although other cell types contribute to its growth and function. These include pre-adipocytes, lymphocytes, macrophages, fibroblasts and vascular cells (Figure 2). AT can respond rapidly and dynamically to nutrient deprivation and also to its excess. One of the unique attributes of AT is its incredible capacity to change its dimensions. This effect can be accomplished by increasing the size of adipose cells (hypertrophy) or by recruiting new adipocytes from the resident pool of progenitors (hyperplasia).

AT expands first by hypertrophy until a critical threshold is reached, upon which signals are released for the induction of preadipocyte proliferation and differentiation (hyperplasia) [17]. Angiogenesis in Adipose Tissue: How can Moderate Caloric Restriction Affects Obesity-Related Endothelial… http://dx.doi.org/10.5772/intechopen.72624 255

Figure 2. Components of adipose tissue [3, 12]. Abbreviations: AT, adipose tissue; ECM, extracellular matrix.

with the uncoupling protein-1 (UCP-1). This provides heat rather than adenosine triphosphate

Omentin-1 Expressed in visceral fat, protects against IR. Its level is reduced in obesity Apelin It plays different functions in various organs. Its production is enhanced by

Adiponectin Negatively correlates with inflammation and visceral fat accumulation,

Secreted frizzled-related protein 5 (SFRP 5) Anti-inflammatory, important for insulin sensitivity

tolerance

protects against metabolic dysfunction and IR

insulin. Has angiogenic and hypotensive properties

Positively correlates with BMI and insulin sensitivity, increases glucose

White adipose tissue (WAT) stores triglycerides during energy consumption and releases fatty acids during starvation. WAT is also an active endocrine organ that secretes a large number of adipokines. Adipokines act centrally to regulate appetite and energy expenditure. They peripherally affect insulin sensitivity, promote subclinical inflammation and lipid uptake and accommodate the conversion of steroid hormones. Fats can be classified as subcutaneous or visceral. WAT has a specific morphology. Histologically, subcutaneous fat contains mature large adipocytes, whereas visceral fat consists of small adipocytes. Subcutaneous and visceral depots contribute to metabolism in different ways. An increased subcutaneous fat deposition in the form of "pear-shaped" or female pattern of distribution might protect against certain aspects of metabolic dysfunction, especially against IR [14, 15]. However, visceral depots, in an "apple" or male pattern of distribution, are thought to be associated with metabolic complications and appear to increase the risk of diabetes, hyperlipidemia and CVD [16]. It has become

AT is mainly comprised of adipocytes, although other cell types contribute to its growth and function. These include pre-adipocytes, lymphocytes, macrophages, fibroblasts and vascular cells (Figure 2). AT can respond rapidly and dynamically to nutrient deprivation and also to its excess. One of the unique attributes of AT is its incredible capacity to change its dimensions. This effect can be accomplished by increasing the size of adipose cells (hypertrophy) or by

AT expands first by hypertrophy until a critical threshold is reached, upon which signals are released for the induction of preadipocyte proliferation and differentiation (hyperplasia) [17].

popular to term subcutaneous adipose as 'good fat' and visceral as 'bad fat'.

recruiting new adipocytes from the resident pool of progenitors (hyperplasia).

(ATP) production [13].

Anti-inflammatory adipokines

Visceral adipose tissue-derived serine

protease inhibitor (Vaspin)

Adipokine Main function

254 Endothelial Dysfunction - Old Concepts and New Challenges

Table 2. Anti-inflammatory adipokines and their functions [11, 12].

3. AT remodeling in obesity

3.1. Infiltration of immune cells into AT

AT remodeling is pathologically accelerated in an obese state with reduced angiogenesis, extracellular matrix (ECM) overproduction and severe immune cell infiltration with subsequent pro-inflammatory responses. The large infiltration of macrophages in AT is linked to a systemic inflammation and IR. Moreover, the accumulation of macrophages is proportional to adiposity, and a sustained weight loss results in the lowering of inflammation, which suggests that this infiltration is reversible. Macrophages are also more abundant in the visceral than subcutaneous AT [6, 12]. Resident adipose macrophages display remarkable heterogeneity in their activities and functions. Hypertrophic adipocytes produce chemotactic factors, which promote monocyte accumulation in AT.

Macrophages can be classified into two broad groups: M1 and M2, based on the expression of particular antigens. Lumeng et al. proposed a model which emphasized that obesity is accompanied by a transformation of M2 anti-inflammatory macrophages (that are primarily accumulated during a negative energy balance) to more pro-inflammatory M1 macrophages [18]. The subsets of T cells presented in AT have been seen to be implicated in the macrophage activation. T helper cells (CD4<sup>+</sup> ) are present in a large numbers in the AT of lean persons and have a protective effect by impeding M1 macrophages, resulting in increased insulin sensitivity. T cytotoxic cell (CD8<sup>+</sup> ) can start the mobilization and activation of M1 macrophages and in this way it promotes an inflammation associated with IR. The M1 population positively correlates with IR and is characterized by overnutrition, where FFAs stimulate its proinflammatory responses [18]. In a lean state, resident macrophages are polarized toward the M2 state, which expresses a combination of anti-inflammatory factors that may help to preserve the normal adipocyte function by promoting AT repair and angiogenesis. Conversely, M1 macrophages induced by pro-inflammatory mediators express a repertoire of proinflammatory factors, which include tumor necrosis factor alpha (TNF-α), interleukin 6 (Il-6), inducible nitric oxidase synthase (iNOS) and produce reactive oxygen species (ROS) [3, 6]. The key function of macrophages is to remove apoptotic cells in an immunologically silent manner to prevent the release of harmful substances. The presence of apoptotic adipocytes surrounded by M1 macrophages (forming the so-called crown-like structures) is a characteristic feature in the obese with a full metabolic dysfunction. This pro-inflammatory state in AT is due to an impairment of the macrophage-mediated phagocytic process. The fibroblasts from metabolically dysfunctional AT produce excess ECM components that may contribute to metabolic dysregulation. The intercellular communication within AT is required for normal metabolic function. The obesity-associated changes in the cellular composition of AT lead to a modification of adipokine secretion [18, 19]. Consequently, obese patients can be categorized into those that have a fully dysfunctional metabolic phenotype and those that have a mildly dysfunctional metabolic phenotype (Figure 3) [19].

tissue, in which the supportive activity of the tissue plasminogen activator system (t-PA and uPA—urokinase-type plasminogen activator) and matrix metalloproteinases (MMPs) are required. Third, the migrated ECs trigger lumen formation as the sprout forms a multicellular structure. Finally, the capillary is stabilized through the construction of a basement membrane,

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http://dx.doi.org/10.5772/intechopen.72624

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AT possesses a relatively dense network of blood capillaries, ensuring an adequate exposure to nutrients and oxygen. The AT vasculature serves to transport systemic lipids to their storage depot in adipocytes, and transfers factors (e.g. adipokines) and nutrients (e.g. FFAs) from these cells in times of metabolic need. The microvasculature of AT is necessary for the expansion of adipose mass not only to prevent hypoxia, but also as a potential source of adipocyte progenitors in WAT. The blood capillary network also contributes to immunity and inflammation. AT macrophages serve multiple functions: (i) removal of necrotic adipocytes, (ii) production of pro-inflammatory and (iii) pro-angiogenic mediators [3, 22]. Obesity reduces the density of capillaries in AT, leading to localized hypoxia. The effect of hypoxia in obesity is complex and could be explained by: (i) the proportion of the cardiac output and blood flow that goes to WAT is not increased in the obese despite the expansion of the tissue mass, (ii) obese subjects do not exhibit the postprandial increase in the blood flow to AT that occurs in lean subjects and (iii) hypertrophied adipocytes are larger than normal, which impedes oxygen delivery to fat cells. Tissue hypoxia drives many cellular and molecular mechanisms. The first cellular mechanism responsible for local inflammation is macrophages recruitment. The necrosis of adipocytes, driven by hypoxia, is a prominent phagocytic stimulus that regulates macrophages infiltration. The second mechanism responsible for adipose inflammation is lipotoxicity. FFAs released from hypertrophic adipocytes could be transported to the liver and stored in lipid droplets. They could also be re-esterified to triglycerides in adipocytes. Those which escape re-esterification play a critical role as a primary energy source in several organs during prolonged fasting. FFAs are also ligands for TLR 4 (Toll-like receptor) presented in macrophages. FFAs binding with TLR 4 activate the inflammatory signaling cascade (NF-κB—nuclear factor kappa-B). The third

mechanism is directly associated with oxygen deprivation (Figure 4) [22–24].

Hypoxia in AT has been investigated in human and animal models. Many adipokines related to inflammation (leptin, TNF-α and Il-6), MMPs, growth factors (VEGF—vascular growth factor and bFGF—basic fibroblast growth factor) are elevated in hypoxia [26]. The master regulator of hypoxia is hypoxia-inducible factor (HIF-1). It is a heterodimer composed of an oxygen-sensitive HIF-1α subunit and a constitutively expressed HIF-1β, which is not directly regulated by oxygen. A substantial number of genes are recognized to be hypoxia sensitive. The target genes include those involved in angiogenesis, cell proliferation, survival, apoptosis, vascular tone, glucose and energy metabolism. The genes, which regulate leptin, VEGF and MMPs expression, are controlled by HIF-1 and become elevated in response to low oxygen partial pressure (pO2) in adipocytes. At the same time, the adiponectin gene is downregulated [27]. Glucose uptake by human adipocytes is strongly stimulated by hypoxia, presumably as a consequence of an increased amount of glucose transporters (GLUT). This may results in changes in insulin sensitivity. An experimental model of intermittent hypoxia has been shown to induce IR [28]. The effect of hypoxia on the WAT function has been discussed in terms of adipocytes, reflecting the fact that these are the cells that are characteristic of AT. Adipocytes

an adherent junction and ECs [20, 21].
