The role of Stat3 signaling in leptin's pleitropic action

DESCRIPTION (provided by applicant): Leptin has potent effects on insulin action, carbohydrate and lipid metabolism, which are largely independent of its effects on feeding behavior. With regard to adipocyte metabolism, leptin leads to a depletion of triglyceride content without a concomitant rise in circulating free fatty acids due to an increase in mitochondrial oxidation and the induction of futile metabolic pathways. Our previous work has revealed that leptin controls adipocyte metabolism by central pathways that descend from the medio-basal hypothalamus (MBH), leading to a strong inhibition of lipogenic gene expression in white adipose tissue (WAT). Remarkably, MBH leptin suppresses the expression and activity of two important transcription factors, sterol-regulatory-element-binding protein-1c (SREBPI-c) and peroxisome proliferator activated receptor (PPAR) gamma, independent of circulating glucose or insulin levels. These effects of central leptin on adipocyte metabolism appear not to require intact signal transducer and activator of transcription (Stat3) signaling, whereas leptin's acute effects on food intake, hepatic glucose fluxes and gonadotropin secretion are lost when Stat3 signaling is prevented. The aim of this proposal is to delineate the contributions of hypothalamic leptin signaling in controlling adipocyte metabolism. We hypothesize that Stat3 independent effects of leptin play a major role in the regulation of adipocyte metabolism and thereby regulate body adiposity. These studies should lead to a better understanding of the basic biological processes by which central pathways regulate body adiposity independently of food intake.