The Metabolic SyndromeFat as an Endocrine Organ: Relationship to the Metabolic Syndrome
Section snippets
Adiponectin
Adiponectin (also referred to as AdipQ, Acrp30, apMI) is expressed and secreted at very high levels in adipocytes.13 Until very recently, this protein was thought to be expressed exclusively in adipocytes43., 44., 45.; however, a few reports now suggest that low levels of adiponectin may also be expressed in other tissues.46., 47., 48. As a result of multimerization this protein is present in the circulation in various molecular weight forms including trimer, hexamer, and a number of high
Leptin
The discovery of leptin by Zhang et al in 199479 resulted in the appreciation of adipose tissue as more than just an inert storage depot for triglyceride. This factor is regarded as the prototypical adipokine, with secretion being regulated by the size of fat stores both in physiologic and pathophysiologic states.80., 81. Leptin is secreted almost exclusively by adipocytes as a 16 kDa product of the ob gene79 and signals via a family of plasma membrane receptors.82., 83. Leptin receptors are
Visfatin
Visfatin (pre-B cell colony-enhancing factor) is a newly identified adipokine that is highly enriched in visceral fat of both humans and mice, and the levels of this 52 kDa secreted protein increase during development of obesity.13., 110. Serum levels of visfatin are positively correlated with degree of visceral adiposity.13 This adipokine exerts insulin-mimetic effects on various tissues including liver, muscle, and fat.111., 112. A recent study reported differential regulation of visfatin
Glucocorticoids
Glucocorticoids play a pivotal role in regulation of fat metabolism, function, and distribution.113 The metabolic syndrome, which includes central obesity, insulin resistance, type 2 diabetes, and dyslipidemia resembles Cushing syndrome; however, unlike this syndrome, the levels of circulating glucocorticoid are not elevated in more common forms of obesity.114 This correlation was intriguing but until recently the role of glucocorticoids in prevalent forms of human obesity was not understood.113
Free Fatty Acids
Plasma levels of free (or non-esterified) fatty acids (FFAs) are elevated in obese individuals, with the major source being visceral adipose tissue.118., 119., 120. The concentrations of FFAs are mainly regulated by catecholamines (favoring lipolysis) and insulin (favoring lipogenesis) and as adipose tissue lipolysis is a major source of FFAs (particularly in obesity), these molecules are regarded as adipokines. Studies in the perfused pancreas demonstrate an involvement of FFAs in insulin
Inflammatory Mediators
Obesity is recognized as a state of low-grade inflammation,13 and recently features of acute-phase activation and low-grade inflammation, including elevated levels of fibrinogen, CRP, and IL-6, have been particularly associated with central or visceral obesity.41 This inflammatory state is a predominant feature in the metabolic syndrome and appears to be linked to vasculopathies and development of diabetes.132 In fact, the chronic inflammation present in obesity has been suggested as a
Tumor Necrosis Factor-Alpha
TNF-α is a proinflammatory adipokine that plays a primary role in stimulating expression of other inflammatory mediators including leptin and IL-6136., 137., 138., 139. whereas expression and secretion of antiinflammatory adiponectin is reduced in response to TNF-α.140., 141. It has been suggested that increased expression of TNF-α in obesity and subsequent reduced expression of adiponectin plays a significant role in development of the metabolic syndrome.142 Expression levels of TNF-α are
Interleukin-6
Interleukin-6 is a 26 kDa protein that functions as an immune-modulating cytokine.154 IL-6 is expressed in adipose tissue and also in hypothalamic nuclei involved in regulation of body composition.155 Adipose tissue contributes a significant proportion of total circulating IL-6,156., 157. with more of this adipokine being released from visceral adipose tissue compared with abdominal subcutaneous tissue.158 The role of IL-6 in the development of obesity and vascular pathology is ambiguous. Some
Plasminogen-Activator Inhibitor 1
Plasminogen-activator inhibitor 1 is a regulatory protein of the coagulation cascade, and elevated levels in inflammatory and obese states are a known risk factor for thrombosis.169 PAI-1 is a serine-protease inhibitor which acts to prevent generation of plasmin thus preventing extracellular matrix degradation and fibrinolysis.13 This decreased fibrinolysis coupled with obesity-induced increases in clotting factors and platelet activation underpin the development of a hypercoagulable state,
Angiotensinogen
Angiotensinogen along with all components of the renin-angiotensin system (RAS), including renin, angiotensin converting enzyme, angiotensin II, and AT-1 and AT-2 receptors, are expressed and secreted from adipose tissue, predominantly visceral depots.34., 176., 177. Several studies have shown that expression and activity of the RAS in adipose tissue, together with plasma levels of angiotensin, are all positively correlated with body fat mass.178., 179., 180. The RAS, with its effects on fluid
Conclusions
Over the past few years, a growing number of adipose-derived factors have been described, and many of these have been implicated in the association between central adiposity, cardiovascular pathology, and comorbidities including systemic inflammation, dyslipidemia, and type 2 diabetes. It is clear that the dysregulated expression and secretion of these adipokines, which occurs in obesity, underpin the vasculopathies and metabolic abnormalities characterizing the metabolic syndrome.
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