**7. Resistin**

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

### **8. Myokines**

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

paracrine, or endocrine effect. Their receptors were found in the muscle, fat, liver, pancreas, bone tissue, heart, brain, and immune cells [33, 34].

Although the endocrine function of adipose tissue has long been recognized, most of the factors produced are pro-inflammatory and harmful in the setting of obesity-induced metabolic disorders and cardiovascular disease. In this regard, adiponectin is relatively unique as an adipokine because it is expressed at highest levels in lean, healthy individuals.

Candidate cDNAs that encode secreted proteins and are differentially regulated in the muscle of the MyoMouse model are then used to construct adenoviral vectors for further testing in animal models of disease. One such factor, follistatin-like 1 (Fstl1), was identified in this type of screen and shown to have cardiovascularprotective properties. Fstl1, also referred to as TSC36, is an extracellular glycoprotein that has been grouped into the follistatin family of proteins [35].

The main myokines studied to date are myostatin, decorin, irisin, myonectin, interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-15 (IL-15), follistatin, fibroblast growth factor 21 (FGF21), bone morphogenetic protein (BMP), and brainderived neurotrophic factor (BDNF). Other possible factors have been detected in the skeletal muscle, but their functions, as well as their presence in the circulation, are largely unknown: musclin and nonneuronal acetylcholine.

### **9. Myostatin**

Also called growth differentiation factor 8 (GDF-8), it is a member of the transforming growth factor-β (TGF-β) family, expressed in developing and adult muscular tissue. It is one of the first described myokines.

Its main function is the negative regulation of the muscle mass, which means high level of myostatin and less muscle mass. It plays a role in stopping myoblast proliferation and suppressing satellite cell activation, inducing muscle atrophy. In addition, it influences the differentiation of muscle fibers by types (fast and slow) and the arrangement of muscle glucose as well as the muscle-adipose tissue crosstalking [36–40].

### **10. Irisin**

Discovered in 2012 as a transmembrane protein, FNDC5 has a cleaved soluble form, irisin, that it is released into circulation during the proteolytic process after acute exercising of skeletal muscles. It increases the energetic and oxidative metabolism of the muscle by activating genes related to these processes. It has a high level during myogenesis and induces glucose uptake improving glucose homeostasis, inhibiting lipid accumulation, and reducing body weight [41, 42]. Irisin has been studied especially in relation to obesity but also with myopathies such as muscular dystrophy. In these latter studies, injection of irisin induced muscle hypertrophy, improving muscle strength and reducing necrosis and development of connective tissue in a murine model [42].

#### **11. Myonectin**

Myonectin is a protein belonging to the C1q/TNF-related protein (CTRP) family, and it is found mainly in the muscle, less in circulation, being especially related to nutritional metabolism. Thus, the expression of myonectin is stimulated

**91**

*Obesity-Related Myocardiopathy*

**13. Adipose tissue expansion**

**14. Immune cell infiltration**

individuals [36].

numbers (hyperplasia).

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

**12. Mechanism of myocardiopathy in obesity**

by exercise and nutrients and is supposed to induce nutrient uptake and storage in other tissues, such as adipose tissue, causing a flux of glucose or fatty acids [42, 43].

Insulin resistance, adiposity, and adipokines have been implicated in the development of abnormal myocardial mechanics in adults with obesity and type 2 diabetes. Adiposopathy in obese individuals is ultimately the consequence of a dysfunctional remodeling of the adipose tissue. Therefore, for understanding how obesity contributes to cardiovascular disease, it is primordial to know how both quantitative and

In response to an excessive caloric intake, the mechanisms by which adipose depots expand represent an important determinant of the risk of cardiovascular disease and metabolic dysfunction. This expansion is mediated by two ways: an enlargement of adipocyte size (hypertrophy) and/or an increase in adipocyte

Adipocyte hypertrophy typically leads to lipid-laden, dysfunctional adipocytes that undergo cell death and contribute to adipose tissue inflammation, dysfunction, and associated pathologies; in contrast it has been classically accepted that hyperplasia allows a "healthy" expansion of the adipose tissue, since it is mediated by the

formation of functional adipocytes from progenitor cells (adipogenesis).

In most cases chronic excessive caloric intake eventually leads to adipocyte dysfunction, regardless of the mechanisms of adipose tissue expansion, and this is paralleled by qualitative and quantitative changes in the composition of adipose tissue at cellular level. Immune cells are of great relevance in this regard. Low-grade chronic inflammation is a major hallmark of adipose tissue in obesity, and it is now known that almost every immune cell type can be found in the adipose tissue. Total numbers of B cells, T cells, neutrophils, macrophages, and mast cells are increased in visceral adipose tissue of obese individuals. In contrast, the number of eosinophils and specific subsets of T cells—T-helper type 2 (Th2) cells and regulatory T (Treg) cells—are decreased or remained static in the adipose tissue of obese

Macrophages are the most abundant immune cell in the adipose tissue of obese individuals, and their recruitment and proliferation upon high-calorie feeding is generally associated with adipose tissue inflammation and insulin resistance [44–47].

Several studies in humans and animal models have shown that obesity induces capillary rarefaction in adipose tissue, and this has been associated with metabolic dysfunction. It is widely a reduced adipose tissue; capillarization is present in obesity, and this reduced blood supply may limit nutrient delivery and contribute to

**15. Impaired vascular structure and function**

adipocyte dysfunction and insulin resistance.

qualitative effects of this adipose tissue remodeling contribute to that.

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

pancreas, bone tissue, heart, brain, and immune cells [33, 34].

tein that has been grouped into the follistatin family of proteins [35].

are largely unknown: musclin and nonneuronal acetylcholine.

muscular tissue. It is one of the first described myokines.

levels in lean, healthy individuals.

**9. Myostatin**

talking [36–40].

tissue in a murine model [42].

**11. Myonectin**

**10. Irisin**

paracrine, or endocrine effect. Their receptors were found in the muscle, fat, liver,

Although the endocrine function of adipose tissue has long been recognized, most of the factors produced are pro-inflammatory and harmful in the setting of obesity-induced metabolic disorders and cardiovascular disease. In this regard, adiponectin is relatively unique as an adipokine because it is expressed at highest

Candidate cDNAs that encode secreted proteins and are differentially regulated in the muscle of the MyoMouse model are then used to construct adenoviral vectors for further testing in animal models of disease. One such factor, follistatin-like 1 (Fstl1), was identified in this type of screen and shown to have cardiovascularprotective properties. Fstl1, also referred to as TSC36, is an extracellular glycopro-

The main myokines studied to date are myostatin, decorin, irisin, myonectin, interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-15 (IL-15), follistatin, fibroblast growth factor 21 (FGF21), bone morphogenetic protein (BMP), and brainderived neurotrophic factor (BDNF). Other possible factors have been detected in the skeletal muscle, but their functions, as well as their presence in the circulation,

Also called growth differentiation factor 8 (GDF-8), it is a member of the transforming growth factor-β (TGF-β) family, expressed in developing and adult

Its main function is the negative regulation of the muscle mass, which means high level of myostatin and less muscle mass. It plays a role in stopping myoblast proliferation and suppressing satellite cell activation, inducing muscle atrophy. In addition, it influences the differentiation of muscle fibers by types (fast and slow) and the arrangement of muscle glucose as well as the muscle-adipose tissue cross-

Discovered in 2012 as a transmembrane protein, FNDC5 has a cleaved soluble form, irisin, that it is released into circulation during the proteolytic process after acute exercising of skeletal muscles. It increases the energetic and oxidative metabolism of the muscle by activating genes related to these processes. It has a high level during myogenesis and induces glucose uptake improving glucose homeostasis, inhibiting lipid accumulation, and reducing body weight [41, 42]. Irisin has been studied especially in relation to obesity but also with myopathies such as muscular dystrophy. In these latter studies, injection of irisin induced muscle hypertrophy, improving muscle strength and reducing necrosis and development of connective

Myonectin is a protein belonging to the C1q/TNF-related protein (CTRP) family, and it is found mainly in the muscle, less in circulation, being especially related to nutritional metabolism. Thus, the expression of myonectin is stimulated

**90**

by exercise and nutrients and is supposed to induce nutrient uptake and storage in other tissues, such as adipose tissue, causing a flux of glucose or fatty acids [42, 43].
