**2. Regional adiposity and cardiovascular risk**

While the cardiovascular risk is linked to the adipose tissue quantity, recent data indicate that differences in fat tissue quality, which can be examined directly by noninvasive computed tomography radiodensity attenuation imaging or by immunohistochemistry, are closely linked to insulin resistance, cardiometabolic risk, and all-cause mortality, independent of total fat volume. These data demonstrate, independent of body mass index, that abnormalities at the adipose tissue level may be key factors that regulate systemic metabolism and drive cardiometabolic disease. These qualitative abnormalities in fat are a growing area of research interest that have been recently termed sick fat or adiposopathy and may in part explain the clinical observation of metabolically healthy obesity. The interindividual variability in adipose tissue "quality" may be related, in part, to differences in lifestyle, as physical activity has effects on adipose tissue physiology and cardiometabolic risk. While animal models of obesity tend to generate fairly uniform phenotypes, the degree of adipose tissue dysfunction in obese humans exhibits significant heterogeneity with lower degrees of adiposopathy being associated with more favorable systemic metabolic profiles and vascular function.

## **3. Adipokines, myokines, and cardiovascular disease**

It is recognized that obesity contributes to cardiovascular and metabolic disorders through alterations in the levels of adipocyte-derived cytokines that are named adipokines.

The functions of adipose tissue are as energy storage and as secretory tissue producing a variety of bioactive substances, including leptin, tumor necrosis factor alpha (TNFα), plasminogen activator inhibitor type 1, and adiponectin [6–9]. These bioactive molecules are generally referred to as adipokines, and several are involved in the pathophysiology of various obesity-linked disorders.

### **4. Leptin**

Leptin is an adipose tissue-specific-secreted hormone and is highly expressed by adipocytes; this adipokine is encoded by the ob gene, which was identified in genetically obese ob/ob mice through positional cloning. The circulating leptin levels increase in parallel to adipose tissue mass. Leptin exerts important metabolic actions by suppressing appetite and increasing energy expenditure. Many lines of evidence suggest that hyperleptinemia contributes to cardiovascular complications. Leptin has pro-inflammatory actions in many immune cell types including monocytes/macrophage, neutrophils, NK cells, and T cells [10–17].

#### **5. Adiponectin**

Adiponectin is abundantly present in human plasma at a range between 3 and 30 μg/mL. It is an adipokine whose mRNA is largely expressed in adipose tissue. Adiponectin multimerizes to form stable higher-order complexes and shares structural homology with the collectin family of proteins.

Lower plasma levels of adiponectin are implicated in the pathogenesis of obesity-related diseases [18–21]. Conversely, plasma adiponectin concentrations

**89**

**7. Resistin**

**8. Myokines**

*Obesity-Related Myocardiopathy*

**6. Interleukin 6**

*DOI: http://dx.doi.org/10.5772/intechopen.85949*

neointimal lesion formation in wild-type mice [30].

ing the spectrum of IL-6 actions and target cells.

overload because of transverse aortic constriction [31, 32].

increase following weight loss [22, 23]. In patients with diabetes mellitus, the levels of adiponectin are lower than patients without diabetes matched for age and weight [14]. An inverse correlation has been demonstrated between circulating levels of

Adiponectin appears to protect against the development of various vascular diseases. In murine experiments, it has been demonstrated that adiponectin has an anti-atherogenic function. In apolipoprotein E-deficient mice, the administration of an adenovirus-expressing adiponectin reduces atherosclerotic lesion size [28]. In apolipoprotein E-deficient mice, the adiponectin deficit leads to an increase in vascular lesion area [29]. Adiponectin knockout mice also develop increased neointimal thickness and display increased vascular smooth muscle cell proliferation following acute arterial injury, whereas overexpression of adiponectin inhibits

Experimental studies have found that adiponectin exerts beneficial actions on the heart under pathological conditions. Adiponectin-deficient mice develop severe cardiac hypertrophy, and there is increased mortality in response to pressure

Interleukin 6 (IL-6) is known to be secreted by several tissues; it is a pleiotropic

cytokine with complex roles in metabolic and cardiovascular disease. IL-6 also can act in a local fashion. However, adipose tissue is a major source of this protein, capable of producing high levels of this protein in the blood. It has been estimated that as much as one-third of total circulating IL-6 originates from adipose tissue.

IL-6-induced cell signaling is typically classified as either classic or transsignaling, and it can lead to different cell responses. In the classic signaling way, the target cells are stimulated by IL-6 stimulates via a membrane-bound IL-6 receptor (IL6R), which upon ligand binding forms a complex with the signaling receptor protein gp130. Essentially all cells exhibit gp130 on the cell surface, whereas few cell types express membrane-bound IL6R. While the cells that only express gp130 are not responsive to IL-6 alone, they can be stimulated, via trans-signaling, by a complex of IL-6 bound to a naturally occurring soluble form of IL6R (sIL6R), markedly expand-

Resistin is highly expressed by mature adipocytes in rodents. This adipokine is a secreted protein that was initially suggested to be a major link between insulin resistance and obesity. Circulating resistin levels are increased in diabetic and obese mice, and the important role of resistin in metabolic dysfunction associated with obesity through pleiotropic effects on insulin sensitivity and glucose metabolism

Myokines have been defined as cytokines and proteins produced and released by myocytes under the action of contractile activity. They exert an autocrine,

has been suggested in several loss- and gain-of-function studies in mice .

Therefore, IL-6 can be considered an adipokine with endocrine actions.

adiponectin and those as C-reactive protein and interleukin 6 [24–27].

#### *Obesity-Related Myocardiopathy DOI: http://dx.doi.org/10.5772/intechopen.85949*

*Visions of Cardiomyocyte - Fundamental Concepts of Heart Life and Disease*

While the cardiovascular risk is linked to the adipose tissue quantity, recent data indicate that differences in fat tissue quality, which can be examined directly by noninvasive computed tomography radiodensity attenuation imaging or by immunohistochemistry, are closely linked to insulin resistance, cardiometabolic risk, and all-cause mortality, independent of total fat volume. These data demonstrate, independent of body mass index, that abnormalities at the adipose tissue level may be key factors that regulate systemic metabolism and drive cardiometabolic disease. These qualitative abnormalities in fat are a growing area of research interest that have been recently termed sick fat or adiposopathy and may in part explain the clinical observation of metabolically healthy obesity. The interindividual variability in adipose tissue "quality" may be related, in part, to differences in lifestyle, as physical activity has effects on adipose tissue physiology and cardiometabolic risk. While animal models of obesity tend to generate fairly uniform phenotypes, the degree of adipose tissue dysfunction in obese humans exhibits significant heterogeneity with lower degrees of adiposopathy being associated with more favorable

It is recognized that obesity contributes to cardiovascular and metabolic disorders through alterations in the levels of adipocyte-derived cytokines that are named

The functions of adipose tissue are as energy storage and as secretory tissue producing a variety of bioactive substances, including leptin, tumor necrosis factor alpha (TNFα), plasminogen activator inhibitor type 1, and adiponectin [6–9]. These bioactive molecules are generally referred to as adipokines, and several are involved

Leptin is an adipose tissue-specific-secreted hormone and is highly expressed by adipocytes; this adipokine is encoded by the ob gene, which was identified in genetically obese ob/ob mice through positional cloning. The circulating leptin levels increase in parallel to adipose tissue mass. Leptin exerts important metabolic actions by suppressing appetite and increasing energy expenditure. Many lines of evidence suggest that hyperleptinemia contributes to cardiovascular complications. Leptin has pro-inflammatory actions in many immune cell types including mono-

Adiponectin is abundantly present in human plasma at a range between 3 and 30 μg/mL. It is an adipokine whose mRNA is largely expressed in adipose tissue. Adiponectin multimerizes to form stable higher-order complexes and shares struc-

Lower plasma levels of adiponectin are implicated in the pathogenesis of obesity-related diseases [18–21]. Conversely, plasma adiponectin concentrations

**2. Regional adiposity and cardiovascular risk**

systemic metabolic profiles and vascular function.

**3. Adipokines, myokines, and cardiovascular disease**

in the pathophysiology of various obesity-linked disorders.

cytes/macrophage, neutrophils, NK cells, and T cells [10–17].

tural homology with the collectin family of proteins.

**88**

adipokines.

**4. Leptin**

**5. Adiponectin**

increase following weight loss [22, 23]. In patients with diabetes mellitus, the levels of adiponectin are lower than patients without diabetes matched for age and weight [14]. An inverse correlation has been demonstrated between circulating levels of adiponectin and those as C-reactive protein and interleukin 6 [24–27].

Adiponectin appears to protect against the development of various vascular diseases. In murine experiments, it has been demonstrated that adiponectin has an anti-atherogenic function. In apolipoprotein E-deficient mice, the administration of an adenovirus-expressing adiponectin reduces atherosclerotic lesion size [28]. In apolipoprotein E-deficient mice, the adiponectin deficit leads to an increase in vascular lesion area [29]. Adiponectin knockout mice also develop increased neointimal thickness and display increased vascular smooth muscle cell proliferation following acute arterial injury, whereas overexpression of adiponectin inhibits neointimal lesion formation in wild-type mice [30].

Experimental studies have found that adiponectin exerts beneficial actions on the heart under pathological conditions. Adiponectin-deficient mice develop severe cardiac hypertrophy, and there is increased mortality in response to pressure overload because of transverse aortic constriction [31, 32].
