Contribution of ATGL in skeletal muscle to lipid metabolism and insulin action

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DESCRIPTION (provided by applicant): Obesity and the metabolic syndrome are global public health problems. These disorders are associated with ectopic deposition of triglycerides (TGs) and other lipid metabolites in non-adipose tissues such as skeletal muscle. Intramyocellular triglyceride (IMTG) accumulation is strongly associated with insulin resistance. The mechanisms underlying IMTG accumulation and its relationship to insulin resistance remain unclear. (ATGL) is a novel adipose-enriched lipase that mediates the initial rate-limiting step in TG hydrolysis. ATGL is also expressed in skeletal muscle, but its role in IMTG hydrolysis has not yet been explored. The central aim of this proposal is to evaluate the role of ATGL in skeletal IMTG hydrolysis and to evaluate the contribution of ATGL- mediated IMTG hydrolysis to lipid and glucose homeostasis. In this proposal, the metabolic consequences of ATGL gain-of-function in skeletal muscle will be evaluated 1) in vitro by generating skeletal muscle-derived C2C12 cells that are stably transfected with retrovirus containing murine ATGL cDNA (C2C12ATGL cells), and 2) in vivo by generating transgenic mice that express murine ATGL cDNA under the control of the skeletal muscle-specific murine muscle creatine kinase promoter (MCK-ATGL mice). Aim 1 will evaluate the effects ATGL overexpression in skeletal muscle on intramyocellular and systemic lipid metabolism. Aim 2 will evaluate the effects ATGL overexpression in skeletal muscle on intramyocellular and systemic glucose metabolism and insulin action. Evaluating the role of ATGL- mediated IMTG hydrolysis will promote the understanding of IMTGs in lipid metabolism and glucose metabolism/insulin action, thereby providing important insights into the pathophysiology and treatment of obesity, insulin resistance, and related metabolic disorders. Obesity and the metabolic syndrome are associated with deposition of excess fat (i.e. triglycerides) in multiple tissues. Fat deposition in skeletal muscle is associated with insulin resistance with can lead to diabetes. Adipose triglyceride lipase (ATGL) has recently been identified as a new enzyme that breaks down fat, but its role in skeletal muscle is not known. Evaluating the role of ATGL-mediated fat breakdown in skeletal muscle will provide important insights into the pathophysiology and treatment of obesity, insulin resistance, and related metabolic disorders.