L234	Adipocyte metabolism in metabolic syndrome.
P.Arner
Department of Medicine at Karolinska Institute, Stockholm, SE.

It has become increasingly evident that disturbed adipose tissue function is an important component in many disorders associated with atherosclerosis.The regulation of adipose tissue function is subject to important species variations and many links between the fat cells and atherosclerosis are human specific. This review will address alterations in adipocyte metabolism and endocrine-like activity that are relevant for man and of potential importance for metabolic syndrome. A major function of fat cells is to store and relase free fatty acids (FFA). The relase is mediated by hydrolysis (lipolysis) if triglycerides in the adipocytes. In metabolic syndrome there is a disturbed lipolysis which is subject to regional adipose variations that are particularly evident when obesity is present as usually is the case in the metabolic syndrome. In the overnight fasting (i.e. basal state) the rate of lipolysis is increased in all regions but most abundantly so in the major subcutaneous area. This elevates the circulating FFA level, which in turn has consequences for liver, muscle and pancreas. A major mechanism for increased basal lipolysis seems to be enhanced production of tumor necrosis factor (TNF) alpha in adipose tissue. This cytokine activates lipolysis through human specific mechanisms. It was recently discovered that an adipocyte specific gene termed CIDEA links TNF-α with lipolysis in a protective fashion. The adipocyte expression of CIDEA is decreased in metabolic syndrome and gene inhibition in human fat cells elevates TNF-α production and lipolysis. The lipolysis action of two major hormone sytems is altered in metabolic syndrome in a region specific manner. The antilipolytic effect is markedly decreased in visceral fat but normal or near normal in the subcutaneous fat; this can be attributed to decreased visceral expression of a major signaling component for insulin namely insulin-like substrate one. The lipolytic effect of catecholamines is increased in visceral adipose tissue but decreased in the subcutaneous area due to multiple abnormalities in signal transduction localized at both receptor and post-receptor levels. This might be induced by a region specific effect of testosterone on catecholamine action. Testosterone inhibits catecholamine signaling in subcutaneous but not in visceral fat cells.In women in particular, metabolic syndrome is often followed by an hyperandrogenic state.The effect of the altered hormonal action on lipolysis is that relatively more FFA are released from visceral than subcutaneous fat during stress, physical activity and meal ingestion. This exposes the liver to high FFA by the portal vein and may cause some of the liver specific alterations in the syndrome. Recently it was discovered that adipose tissue also secretes a number of proteins that have peripheral effects. Several are cytokines such as TNF-α mentioned above, which impair insulin action. Others are hormones which alter energy balance (leptin) or insulin action (adiponectin). The production of these proteins is markedly altered in adipose tissue of metabolic syndrome patients but the regulatory events are less well recognized. It may be, though that they are a component of the low grade inflammatory state of adipose tissue that accompanies the metabolic syndrome. In conclusion, alterations in lipolysis and protein secreion by adipose tissue are key components in the pathophysiology of the metabolic syndrome

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