27 LEPTIN REGULATES ADIPOSE TISSUE LIPOGENESIS THROUGH HYPOTHALAMIC PATHWAYS THAT REQUIRE PI3K BUT ARE INDEPENDENT OF STAT3 SIGNALING.

Adipose tissue metabolism is a major factor in the control of body fat mass. In the long term, the size and the metabolism of our adipose depots have a pivotal impact on glucose fluxes and insulin resistance. A better understanding of the regulatory pathways that control body adiposity will improve our understanding of the association between obesity and insulin resistance, with implications for the pathophysiology and treatment of diabetes. Leptin regulates fuel partitioning by promoting lipid oxidation and protein synthesis and by curtailing lipogenesis, resulting in a selective loss of adiposity while preserving lean body mass. Here we examined whether the central administration of leptin modulates the expression of key lipogenic enzymes in visceral fat pads. Because insulin and glucose can also alter the expression of these genes and central leptin is known to affect both, all rats received a 6-hour infusion of leptin or vehicle into the mediobasal hypothalamus (MBH) while the circulating glucose and insulin levels were kept constant at basal levels in all groups (pancreatic basal insulin clamp). Central administration of leptin to conscious rats markedly down-regulated the adipose tissue expression of several key lipogenic enzymes, including acetyl-CoA carboxylase (ACC), stearoyl desaturase 1 (SCD1), and fatty acid synthase (FAS) at the protein and mRNA levels, as well as the incorporation of palmitate into adipose triglycerides. This coincides with the rapid suppression of sterol regulatory element binding protein 1c (SREBP-1c) and peroxisome proliferator-activated receptor (PPARγ) mRNA in adipose tissue, independent of circulating insulin and glucose levels. In a series of studies in which we selectively obliterated the STAT3 or PI3K pathway of the leptin receptor in the hypothalamus using either a cell-permeable peptide inhibitor of STAT3 or the PI3K inhibitor LY294002, we found that the effects of MBH leptin on adipose tissue lipogenesis are dependent on the central activation of PI3K but not STAT3. We further analyzed the body composition in a genetic model (s/s mice) in which the leptin receptor carries a S1138A mutation that renders it unable to signal through STAT3 while leaving its other proximal signaling pathways intact and compared it with db/db mice (complete inactivation of all leptin receptor signaling). Interestingly, after 2 months of pairfeeding, the s/s mice have lower body fat but conserved lean body mass, further supporting the hypothesis that STAT3-independent signaling pathways regulate adipocyte lipogenesis. These findings contrast with our recent work that demonstrated that the control of hepatic glucose fluxes, food intake, and gonadotropin secretion by central leptin critically depends on intact STAT3 signaling. Thus, this work unveils a crosstalk between STAT3-independent signaling in the MBH and adipose tissue lipid metabolism that occurs independently of food intake or circulating insulin and glucose levels. Furthermore, these results demonstrate that central pathways can rapidly modulate the expression of transcription factors such as SREBP1c and PPARγ by as yet unidentified mechanisms.