Cardiology Research and Practice is similar to that used by insulin to promote increased production of NO in vascular endothelium. Moreover, we have demonstrated that intra-arterial ghrelin administration acutely improves endothelial dysfunction by increasing nitric oxide (NO) and decreases ET-1-dependent vasoconstriction, thereby restoring the physiological balance between these opposing vascular mediators in patients with central obesity [57, 58]. Thus, therapeutic interventions including weight loss, exercise, or pharmacological therapies that increase plasma ghrelin levels could to contribute to this strategies by mimicking and/or augmenting beneﬁcial eﬀects of increased insulin sensitivity. Dysregulation of adipokines synthesis and release into the blood stream occur in obese patients and play a critical role in promoting IR [59–61]; diabetes and dyslipidemia are characterized by low adiponectin levels and elevated levels of inﬂammatory adipokines such as TNF-alpha (TNF-α) [62]. Adipose tissue also expresses a local renin-angiotensin system (RAS). Adipocytes express RAS receptors and syn- thesize and secrete angiotensinogen and angiotensin peptides [63]. RAS is a hormonal cascade that governs vascular tone, ﬂuid-electrolyte balance, and blood pressure [64]. 4. Adipokines and Cardiac Function Many studies have shown eﬀects on the heart of various adipokines. TNF-α has been considered to be a critical factor in the pathogenesis of cardiac contractile dysfunction and heart failure. Transgenic mice with overexpression of TNF-α develop severe dilated cardiomyopathy [11], and TNF-α directly depresses cardiomyocyte contractility and induces apoptosis of cardiomyocytes in vitro [65]. TNF-α has negative inotropic eﬀects on cardiomyocytes in vitro, and leads to heart failure in mice [66–72]. In addition, elevated serum TNF-α levels have been associated with the progression of heart failure in patients [66]. Experimental ﬁndings have shown that adiponectin has several beneﬁcial eﬀects in the cardiovascular system. Adiponectin plays an essential role in the maintenance of heart architecture, as the cytokine may attenuate angiotensin II-induced cardiac hypertrophy [73] and attenuate car- diomyocyte contractile dysfunction in db/db diabetic obese mice via a mechanism possibly related to c-Jun and IRS-1 phosphorylation [74]. Moreover, adiponectin represses atherosclerotic lesions in a mouse model of atherosclerosis, and adiponectin- deﬁcient mice exhibit an accelerated vascular remodeling response to injury [75]. In addition, adiponectin stimulates nitric oxide production in endothelial cells through AMPK- dependent and AMPK-independent phosphorylation of endothelial nitric oxide synthase (eNOS) [76, 77] and hypoadiponectinemia is associated with the progression of left ventricular hypertrophy (LVH), which is accompanied by diastolic dysfunction [78]. An association between serum leptin concentrations and various cardiovascular risks, including myocardial infarction [79], coronary heart disease [40], stroke [39], chronic heart 3 failure [80], and left cardiac hypertrophy [81], has been observed. Several works suggested that leptin could be an impor- tant link between obesity and development of cardiovascular disease [82]. This might be mediated through various eﬀects of leptin including eﬀect on blood pressure [83], inﬂamma- tory vascular response [42, 84], and platelet aggregation [85, 86]. High levels of leptin are associated with lower arterial distensibility [87] and have also been shown by several inves- tigators to promote angiogenesis, enhance the calciﬁcation of vascular cells, and potentiate the prothrombotic platelet aggregation [86, 88] moreover, obese individuals possess higher plasma levels of prothrombotic factors such as ﬁb- rinogen, von Willebrand factor, factor VII, and plasminogen activator inhibitor-1 (PAI-1), which lead to a higher risk of thrombosis and atherosclerosis. The levels of pro-thrombotic factors such as ﬁbrinogen, von Willebrand factor, factor VII, and plasminogen activator inhibitor-1 (PAI-1) are shown to be directly correlated with leptin levels [89]. Ghrelin is not produced by the adipose tissue; however, the functions of this gastric peptide are closely related to those of adipokine regarding metabolic and cardiovascular function. Ghrelin has been demonstrated to have cardiovascular eﬀects, both in animals and humans. Ghrelin protects the heart from ischemia in rats, and chronic administration of the peptide improves cardiac contractility in animals with chronic heart failure [90]. Furthermore, in the heart of rats subjected to ischemia followed by reperfusion, ghrelin reduces the infarct size [91], increases cardiac output, diastolic thickness of the noninfarcted wall, and attenuates the development of cardiac cachexia in rats with heart failure [92]. In humans, ghrelin administration reduces cardiac afterload and increases cardiac output and systemic vascular resistance, without changing heart rate [93]. Moreover, ghre- lin administration increases exercise capacity and improves left ventricular function and muscle wasting in patients with chronic heart failure [94–96]. 5. Adipose Tissue Inﬂammation Recent observations from Kamei et al. [97] on transgenic mice have led to the concept that obesity contributes to IR and diabetes promoting a condition of chronic, low-grade inﬂammation of the adipose tissue because of additional inﬁltration and accumulation of inﬂammatory macrophages [98–102]. The macrophage content of adipose tissue is higher in visceral obesity compared to subcutaneous obesity, leading to the concept that visceral fat more than subcutaneous one plays a central role in the development of IR [103]. Macrophages appear to be recruited from the circulation, and adipocyte-derived factors might be involved in this process. Monocyte chemoattractant protein-1 (MCP-1) is pro- duced predominantly by macrophages and endothelial cells and is considered one of the most important potent chemotactic factors for monocytes. The increase of MCP-1 expression in adipose tissue contributes to the macrophage inﬁltration and IR associated with obesity.