G0/G1 switch gene-2 regulates human adipocyte lipolysis by affecting activity and localization of adipose triglyceride lipase

Abstract

Supplementary key words comparative gene identifi cation-58 • human lipolysis • regulation • insulin resistanceIn periods of nutrient scarcity or in response to increased energy demand, triglyceride (TG) stores are mobilized to provide free fatty acids (FFAs) as energy fuel. The mobilization of TGs is performed in three consecutive reactions, catalyzed by three lipases: adipose triglyceride lipase (ATGL) ( 1-3 ), hormone-sensitive lipase (HSL) ( 4 ), and monoglyceride lipase (MGL) ( 5 ). The crucial physiological role of ATGL (also annotated as patatin-like phospholipase domain containing 2, desnutrin, phospholipase A2 , and transport secretion protein 2.2) in lipolysis became evident by the phenotype of ATGL-defi cient (ATGL-ko) mice. ATGL-ko mice display increased whole-body fat mass, enlarged adipose fat depots, and TG accumulation in many tissues. Massive TG deposition in cardiomyocytes leads to cardiac insuffi ciency and premature death ( 6 ). In humans, 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.ATGL activity is strongly infl uenced by regulatory proteins. In 2006, Lass et al. identifi ed comparative gene identifi cation-58 (CGI-58, also known as ABHD5) as coactivator of 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 identifi cation-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. -Schweiger, M., M. Paar, C. Eder, J. Brandis, E. Moser, G. Gorkiewicz, S. Grond, F. P. W. Radner, I. Cerk, I. Cornaciu, M. Oberer, S. Kersten, R. Zechner, ...

Defective Adipose Lipolysis and Altered Global Energy Metabolism in Mice with Adipose Overexpression of the Lipolytic Inhibitor G0/G1 Switch Gene 2 (G0S2)

“…In agreement with the previous studies demonstrating G0S2 as a specific inhibitor of ATGL (25)(26)(27), transgenic expression of G0S2 was able to inhibit adipose lipolysis under both basal and stimulated conditions. The supporting evidence include the following: (i) circulating FFA levels in aP-G0S2 mice on both chow and HFD were lower than those in the wild type mice during the fed state; (ii) an overnight fast or acute treatment with a ␤3-adrenergic agonist decreased plasma FFA concentration to a greater extent in aP2-G0S2 mice than in wild type mice; and (iii) basal and stimulated release of FFA and glycerol was significantly decreased from ex vivo cultured fat pads isolated from aP2-G0S2 mice.…”

Mice lacking G0S2 are lean and cold-tolerant

“…G0S2 is abundantly expressed in adipose tissue, and is also expressed in other tissues such as liver and hematopoietic cells. [2][3][4][5] When acute promyelocytic leukemia (APL) cells were treated with all-trans retinoic acid to induce differentiation and reduce tumorigenicity, G0S2 levels were markedly induced. 6 Transcriptional regulation of G0S2 is cell context-dependent.…”

Cardiac-specific overexpression of perilipin 5 provokes severe cardiac steatosis via the formation of a lipolytic barrier

“…TG hydrolytic activities were measured in a combination of cell lysates containing LacZ, ATGL, and Plin5. We also included COS-7 cell lysates containing G0S2, a known inhibitory protein of ATGL ( 37,38 ). TG hydrolytic activities substantially increased in cell preparations containing ATGL (up to 11.6-fold compared with the LacZ control) independent of whether ATGL-containing cell lysates were mixed with lysates containing LacZ or Plin5 ( Fig.…”