2. Adipose tissue

AT was earlier characterized as a connective tissue which stores triglycerides. An increase in global obesity and diabetes has attracted great interest to the function of this tissue. Nowadays, AT is considered an important regulator of energy balance, which plays a major role in nutrient homeostasis after feeding and releases free fatty acids (FFAs) during fasting. As such, it is regarded as an endocrine organ producing adipokines, which affect many organs and thus the homeostasis in the body (Figure 1).

AT is mainly found in subcutaneous and visceral depots. In obesity, AT is accumulated in different organs, including heart, liver, kidneys, bone marrow, lungs and the adventitia of major blood vessels, where secreted adipokines affect their function. Excess visceral adiposity is strongly correlated with IR, hypertension and dyslipidemia, which contribute to high rates of mortality and morbidity [3, 10]. Most adipokines, which stimulate inflammatory responses, are dysregulated in obesity and promote obesity-induced metabolic dysfunction, leading to CVD. The production of pro-inflammatory cytokines by AT is upregulated in an obese state (Table 1) while the secretion of anti-inflammatory factors is reduced (Table 2).

Adipocytes are divided into two types: white adipocytes and brown adipocytes. Brown adipocyte tissue (BAT) converts nutrients into chemical energy in the form of heat. Brown fat cells express a unique thermogenic and mitochondrial genetic program that promotes mitochondrial biogenesis, energy uncoupling and energy dissipation, in turn providing essential heat to the organism. Energy dissipation is possible in the presence of large amounts of mitochondria

Chemerin Inflammation, involved in monocyte chemotaxis and stimulates lipolysis

monocyte chemoattractant

Figure 1. The impact of adipose tissue on multiple organs mediated by various factors released from adipocytes [3].

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Resistin Induces insulin resistance by stimulating the Il-6 and TNF-α production in macrophages Retinol-binding protein 4 (RBP4) Induces insulin resistance by influencing glucose homeostasis

Angiopoietin-like protein 2 (ANGPTL-2) Activates inflammatory response in endothelium and promotes insulin

Interleukin 6 (Il-6) Involved in insulin resistance. It has various function in different organs Interleukin 18 (IL-18) Inflammation, involved in plaque instability and endothelial activation

Inflammation, involved in monocyte chemotaxis

resistance Tumor necrosis factor-α (TNF-α) Attenuates insulin signaling in muscles and adipose tissue (IR)

CXC-chemokine ligand 5 (CXCL5) Secreted from macrophages in AT. Responsible for IR

Promotes insulin resistance through TNF-α secretion from adipocytes

Modulator of B cell differentiation, correlates with visceral adiposity,

Leptin Appetite control though the central nervous system

Pro-inflammatory adipokines

lipocalin)

(MCP-1/CCL-2)

(NAmPT, Visfatin)

Adipokine Function

Lipocalin 2 (neutrophil gelatinase-associated

Monocyte chemoattractant protein 1

Nicotinamide phosphor ribosyltransferase

Table 1. Pro-inflammatory adipokines and their functions [11, 12].

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Figure 1. The impact of adipose tissue on multiple organs mediated by various factors released from adipocytes [3].


body [1]. Central obesity is associated with insulin resistance (IR) and this condition predisposes to cardiovascular disease (CVD) [2]. Adipose tissue (AT) is not only an energy storage organ but also produces adipokines, which contribute to the development of subclinical inflammation [3]. The compounds released from AT are capable of affecting endothelial cell (EC) functions [4]. The mechanism of obesity-induced endothelial dysfunction is multifactorial mainly due to the omnidirectional impact of various adipokines, leading to the following abnormalities such as elevated blood pressure, formation of atherosclerotic plaques, oxidative stress, prothrombotic state and alterations in glucose and lipid metabolism [5]. AT remodeling is pathologically accelerated in an obese state due to local hypoxia. Reduced angiogenesis is a severe immune cell infiltration with subsequent pro-inflammatory responses which additionally deteriorates EC functions [6]. Therefore, one of the main goals of therapeutic interventions in obesity is to correct abnormalities in EC function and to protect endothelial integrity.

It is believed that EC dysfunction in obesity can be reduced by caloric restriction (CR), but it is unclear whether this benefit requires significant or moderate weight loss. In recent studies conducted on overweight humans, short- and long-lasting CR (6–52 weeks) have shown to improve a number of health outcomes [7–9]. The important issue is that most individuals have difficulty sustaining prolonged CR and the improvement of EC function may be problematic to achieve. Our cooperation with physicians, dieticians and psychologists allows us to claim that it is usually optimal for obese patients if CR is not so burdensome and yet, at the same time, effective. Therefore, we propose a mild CR as a way to lose body weight in obese individuals. Such a type of CR reflects a real-life situation and seems to be optimal to achieve

AT was earlier characterized as a connective tissue which stores triglycerides. An increase in global obesity and diabetes has attracted great interest to the function of this tissue. Nowadays, AT is considered an important regulator of energy balance, which plays a major role in nutrient homeostasis after feeding and releases free fatty acids (FFAs) during fasting. As such, it is regarded as an endocrine organ producing adipokines, which affect many organs and thus

AT is mainly found in subcutaneous and visceral depots. In obesity, AT is accumulated in different organs, including heart, liver, kidneys, bone marrow, lungs and the adventitia of major blood vessels, where secreted adipokines affect their function. Excess visceral adiposity is strongly correlated with IR, hypertension and dyslipidemia, which contribute to high rates of mortality and morbidity [3, 10]. Most adipokines, which stimulate inflammatory responses, are dysregulated in obesity and promote obesity-induced metabolic dysfunction, leading to CVD. The production of pro-inflammatory cytokines by AT is upregulated in an obese state

Adipocytes are divided into two types: white adipocytes and brown adipocytes. Brown adipocyte tissue (BAT) converts nutrients into chemical energy in the form of heat. Brown fat cells

(Table 1) while the secretion of anti-inflammatory factors is reduced (Table 2).

an improvement of EC.

2. Adipose tissue

the homeostasis in the body (Figure 1).

252 Endothelial Dysfunction - Old Concepts and New Challenges


Table 1. Pro-inflammatory adipokines and their functions [11, 12].

express a unique thermogenic and mitochondrial genetic program that promotes mitochondrial biogenesis, energy uncoupling and energy dissipation, in turn providing essential heat to the organism. Energy dissipation is possible in the presence of large amounts of mitochondria


Anti-inflammatory adipokines

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

with the uncoupling protein-1 (UCP-1). This provides heat rather than adenosine triphosphate (ATP) production [13].

> 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

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

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

have a protective effect by impeding M1 macrophages, resulting in increased insulin sensitiv-

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

) are present in a large numbers in the AT of lean persons and

) can start the mobilization and activation of M1 macrophages and in

promote monocyte accumulation in AT.

activation. T helper cells (CD4<sup>+</sup>

ity. T cytotoxic cell (CD8<sup>+</sup>

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