Insulin controlled secretory function of adipocytes

Obesity and type 2 diabetes are emerging as major public health problems. Adipocytes secrete physiologically active proteins (adipokines), many of which play important roles in the pathophysiology of obesity and type 2 diabetes. At the molecular level, insulin controls secretion of fatty acids and adipokines via a number of evolutionarily conserved signaling pathways. However, understanding the role of insulin in the regulation of adipocyte secretion is still elusive.;Adipose-derived hormone, leptin, plays a central role in regulation of body weight and energy expenditure. Secretion of leptin increases after feeding and decreases after food deprivation. The connection between nutrient intake and the level of leptin secretion remains largely unknown. We have tested the hypothesis that leptin expression in the adipocyte is regulated by nutrient and insulin-sensitive mammalian target of rapamycin complex 1 (mTORC1)-mediated pathway. Using metabolic labeling, we found that mTORC1 increases leptin production at the level of translation. In contrast to previously described models, this regulation does not require the presence of either the 5'-terminal oligopyrimidine tract or the 5'-untranslated region in leptin mRNA.;As opposed to leptin production, mobilization of free fatty acid by lipolysis is activated during energy deprivation and is suppressed by nutrients and insulin. We have shown that mTORC1 inhibits lipolysis and promotes triglycerides accumulation both in vivo and in vitro. The effect of mTORC1 on lipolysis is attributed to the inhibition of expression of the rate-limiting lipolytic enzyme, adipocyte triglyceride lipase, ATGL. Thus, mTORC1 signaling in adipose cells is largely responsible for the role that fat tissue plays in the regulation of metabolic and energy homeostasis in the body. We have found, however that mTORC1 only partially confers the inhibitory effect of insulin on ATGL expression. Using reporter gene expression analysis, chromatin immunoprecipitation, siRNA mediated knock-down and lentiviral mediated protein over-expression, we discovered that ATGL represents a direct target of the insulin regulated transcription target forkhead box O (FoxO1). This finding establishes FoxO1 as a central regulator of the adaptive response to fasting at the level of the whole organism. Our results uncover the molecular mechanisms of insulin-meditated reciprocal regulation of leptin production and lipolysis in adipocyte.