Abstract
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-δ (PPARδ) by lipolysis products. 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 PPARδ-target genes, and highlight an important metabolic function of CGI-58 in skeletal muscle.
Highlights
We investigated here the specific role of CGI-58 in the regulation of energy metabolism in skeletal muscle
We investigated the ability of human recombinant CGI-58 to induce Triacylglycerol hydrolase (TAGH) activity (TAGH) in human adipose tissue (AT) and skeletal muscle (SkM) lysates (Fig. 1C)
We identify that the Adipose triglyceride lipase (ATGL) coactivator CGI-58 has a master regulator of human skeletal muscle TAG metabolism
Summary
We investigated here the specific role of CGI-58 in the regulation of energy metabolism in skeletal muscle. This regulation involves the activation of the peroxisome proliferator activating receptor-␦ (PPAR␦) by lipolysis products 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␦-target genes, and highlight an important metabolic function of CGI-58 in skeletal muscle.—Badin, P-M., C. Recent work indicates that the rate-limiting step for the mobilization of intracellular TAG is the release of CGI-58 from specific lipid droplet scaffold proteins such as Perilipin-A [6] Together, these data suggest that CGI-58 may be important for the control of lipolysis in several tissues. ATGL-deficient mice exhibit a defective TAG hydrolase activity in skeletal muscle and accumulate large amount of TAG in various tissues [1] These data suggest that ATGL may play an important role in the regulation of IMTG and lipolysis notably in skeletal muscle. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health or other granting agencies
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