Regulation of skeletal muscle lipolysis and oxidative metabolism by the co-lipase CGI-58

We investigated here the specific role of CGI-58 in the regulation of energy metabolism in skeletal muscle. We first examined CGI-58 protein expression in various muscle types in mice, and next modulated CGI-58 expression during overexpression and knockdown studies in human primary myotubes and evaluated the consequences on oxidative metabolism. We observed a preferential expression of CGI-58 in oxidative muscles in mice consistent with triacylglycerol hydrolase activity. We next showed by pulse-chase that CGI-58 overexpression increased by more than 2-fold the rate of triacylglycerol (TAG) hydrolysis, as well as TAG-derived fatty acid (FA) release and oxidation. Oppositely, CGI-58 silencing reduced TAG hydrolysis and TAG-derived FA release and oxidation (-77%, P < 0.001), whereas it increased glucose oxidation and glycogen synthesis. Interestingly, modulations of CGI-58 expression and FA release are reflected by changes in pyruvate dehydrogenase kinase 4 gene expression. This regulation involves the activation of the peroxisome proliferator activating receptor-delta (PPAR delta) by lipolysis products.jlr Altogether, these data reveal that CGI-58 plays a limiting role in the control of oxidative metabolism by modulating FA availability and the expression of PPAR delta-target genes, and highlight an important metabolic function of CGI-58 in skeletal muscle.-Badin, P-M., C. Loubiere, M. Coonen, K. Louche, G. Tavernier, V. Bourlier, A. Mairal, A. C. Rustan, S. R. Smith, D. Langin, and C. Moro. Regulation of skeletal muscle lipolysis and oxidative metabolism by the co-lipase CGI-58. J. Lipid Res. 2012. 53: 839-848.