Inhibition of ATGL-Mediated Lipolysis by G0S2

The rate of free fatty acid (FFA) release from adipose tissue in humans and rodents is strongly associated with the development of obesity and type 2 diabetes, but the mechanisms that regulate the FFA release from stored fat remain insufficiently understood. Our preliminary studies provide compelling evidence that a protein encoded by GO/G1 switch gene 2 (GOS2) is a selective regulator of adipose triglyceride lipase (ATGL), the ratelimiting enzyme for triacylglycerol (TAG) hydrolysis/mobilization. GOS2 is highly expressed in adipose tissue and differentiated adipocytes. It specifically interacts with ATGL, leading to the inhibition of its TAG lipase activity. Knockdown and overexpression experiments demonstrate that GOS2 functions to attenuate ATGLmediated lipolysis in both adipocytes and nonadipocyte cells. The overall goal of this proposal is to further explore the molecular details of ATGL inhibition by GoSz, and more importantly, the physiologic roles of GoSz in TAG lipolysis in the context of various functional settings ...1....