Abstract
The hydrolysis of triglycerides in adipocytes, termed lipolysis, provides free fatty acids as energy fuel. Murine lipolysis largely depends on the activity of adipose triglyceride lipase (ATGL), which is regulated by two proteins annotated as comparative gene identification-58 (CGI-58) and G0/G1 switch gene-2 (G0S2). CGI-58 activates and G0S2 inhibits ATGL activity. In contrast to mice, the functional role of G0S2 in human adipocyte lipolysis is poorly characterized. Here we show that overexpression or silencing of G0S2 in human SGBS adipocytes decreases and increases lipolysis, respectively. Human G0S2 is upregulated during adipocyte differentiation and inhibits ATGL activity in a dose-dependent manner. Interestingly, C-terminally truncated ATGL mutants, which fail to localize to lipid droplets, translocate to the lipid droplet upon coexpression with G0S2, suggesting that G0S2 anchors ATGL to lipid droplets independent of ATGL's C-terminal lipid binding domain. Taken together, our results indicate that G0S2 also regulates human lipolysis by affecting enzyme activity and intracellular localization of ATGL. Increased lipolysis is known to contribute to the pathogenesis of insulin resistance, and G0S2 expression has been shown to be reduced in poorly controlled type 2 diabetic patients. Our data indicate that downregulation of G0S2 in adipose tissue could represent one of the underlying causes leading to increased lipolysis in the insulin-resistant state.
Highlights
The hydrolysis of triglycerides in adipocytes, termed lipolysis, provides free fatty acids as energy fuel
As observed for human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes, in murine 3T3-L1 adipocytes, adipose triglyceride lipase (ATGL) and tentatively G0/G1 switch gene-2 (G0S2) expression was induced by rosiglitazone, which was not observed for comparative gene identification-58 (CGI-58) protein expression
This indicates that expression of ATGL and G0S2, but not of CGI-58, is induced during differentiation of human and murine adipocytes by the peroxisome proliferator-activated receptor-␥ (PPAR-␥) activator rosiglitazone
Summary
The hydrolysis of triglycerides in adipocytes, termed lipolysis, provides free fatty acids as energy fuel. G0/G1 switch gene-2 regulates human adipocyte lipolysis by affecting activity and localization of adipose triglyceride lipase. The lack of ATGL activity, caused by mutations in the ATGL gene, is associated with a rare inherited disorder, annotated as neutral lipid storage disease with myopathy (NLSDM) [7]. This disease is characterized by TG deposition in multiple tissues and cardiac myopathy. The significance of this activity in the development of the severe skin defect in mice lacking CGI-58 or in patients suffering NLSDI is unclear
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