LIPOTOX

Obesity and type 2 diabetes mellitus (T2DM) have been associated with an ectopic fat deposition in non-adipose tissues such as skeletal muscle which plays an important role in the etiology of insulin resistance. Ectopic lipids mainly accumulate as triacylglycerol (TAG) in skeletal muscle. An inverse association between intramyocellular TAG (IMTG) content and peripheral glucose disposal (measured by euglycemic hyperinsulinemic clamp) has been repeatedly reported. It is now well established that IMTG is associated with elevated levels of lipotoxic intermediates such as diacylglycerol (DAG) and ceramide that inhibit insulin action and interfere with glucose metabolism. However, how IMTG mediates lipotoxicity in sedentary subjects is poorly understood so far. We propose the novel hypothesis that a dysregulation of the breakdown of IMTG by metabolic lipases can contribute to lipotoxicity and insulin resistance. This hypothesis is supported by unpublished data in humans collected over the last three years during my postdoctoral stay at the Pennington Biomedical Research Center (Baton Rouge, Louisiana). This project aims to investigate the role of skeletal muscle lipases in metabolic diseases such as obesity and T2DM. The central aim of this proposal is to evaluate the role of metabolic lipases in skeletal IMTG hydrolysis and to evaluate the contribution of lipases-mediated IMTG hydrolysis to lipid and glucose homeostasis. In this proposal, the metabolic consequences of ATGL/CGI-58 and HSL gain-of-function and loss-of-function in skeletal muscle will be evaluated 1) in vitro by investigating the impact of ATGL/CGI-58 and HSL gain- and loss-of-function on lipid and glucose metabolism in human primary myotubes, and 2) in vivo by generating transgenic mice that express murine CGI-58 and HSL cDNA under the control of the skeletal muscle-specific murine creatine kinase promoter (MCK-CGI-58 and MCK-HSL mice). The role of metabolic lipases in the regulation of IMTG breakdown, lipotoxicity and insulin sensitivity in skeletal muscle is underappreciated and has been poorly investigated so far. Evaluating the role of metabolic lipases in the regulation of IMTG hydrolysis will allow the understanding of the role of IMTG in lipid and glucose metabolism as well as insulin action, thereby providing important insights into the pathophysiology and treatment of obesity, insulin resistance, and related metabolic disorders.