G0/G1 switch gene 2 has a critical role in adipocyte differentiation

Abstract

Mouse 3T3-L1 preadipocytes differentiate into adipocytes when treated with 3-isobutyl-1-methylxanthine, dexamethasone, and insulin. Although mechanisms of adipogenesis, including transcriptional cascades, are understood, it is still unclear how clonally expanded cells eventually enter the terminal differentiation program. From gene expression profile studies, we identified G0/G1 switch gene 2 (G0s2) as a novel regulator of adipogenesis. The gene was found to be expressed at a higher level in white and brown adipose tissues, and it was induced in 3T3-L1 cells by hormonal treatment. Importantly, G0s2 expression was closely associated with the transition from mitotic clonal expansion to terminal differentiation. Knockdown of G0s2 expression with siRNA inhibited adipocyte differentiation, whereas constitutive overexpression of G0s2 accelerated differentiation of preadipocytes to mature adipocytes. Expression of G0s2 was found to be regulated by peroxisome proliferator-activated receptor c (PPARc), which is a well-known regulator of adipocyte differentiation. Absence of either PPARc or G0s2 expression resulted in apoptotic pathway activation before terminal differentiation. To determine whether G0s2 has a role in vivo, G0s2-knockout mice were generated. The knockout mice were normal in appearance, but they had less adipose mass than wild-type littermates. Mouse embryonic fibroblast cells from G0s2-deficient mice exhibited impaired adipogenesis and contained unusually small intracellular lipid droplets, suggesting that G0s2 has a role in lipid droplet formation. Our studies demonstrate that G0s2 has an important role in adipogenesis and accumulation of triacylglycerol.

Regulation of fibroblast lipid storage and myofibroblast phenotypes during alveolar septation in mice

“…G0S2 is expressed in the lung and is abundant in adipose cells, and its expression increases during differentiation from preadipocytes to mature adipocytes. In these mature cells, G0S2 inhibits adipose triglyceride lipase and controls the size of cytoplasmic lipid droplets (11,19,20). Others have reported that the expression of G0S2 is diminished at P8 in lungs from mice bearing a compound deletion of both FGFR3 and FGFR4, which exhibit defective alveolarization (54).…”

A Peptide Derived from G0/G1 Switch Gene 2 Acts as Noncompetitive Inhibitor of Adipose Triglyceride Lipase

“…To date, no mutation in human G0S2 has been reported. Global and liver-specific G0s2 -KO mouse models were generated very recently and display decreased adipose tissue mass ( 24 , 25 ), enhanced lipolysis in adipose tissue, and a decrease in hepatic TG content ( 26 ). Global and adipose tissue-specific overexpression of G0S2 leads to increased fat mass, overall reduction in lipolytic activity, and fatty liver ( 16 , 19 , 26 ).…”

G0S2: A small giant controller of lipolysis and adipose-liver fatty acid flux

“…Successive studies confirmed high-level expression of G0S2 in adipose tissue of adult humans and animals including mice, pigs, bears and avian species [68, 72–77]. In cultured human SGBS and mouse 3T3-L1 pre-adipocyte cell lines, both G0S2 mRNA and protein have been shown to exhibit adipogenesis-dependent expression [45, 61, 72, 75]. In humans, G0S2 mRNA expression in subcutaneous adipose tissue was found to be 7 times higher in mature adipocytes than in the cells of corresponding stroma-vascular fraction [77].…”

“…Sequence analysis revealed that the G0S2 promoter region encompasses a potential PPAR-responsive element (PPRE), and Zandbergen et al subsequently provided evidence that G0S2 expression in adipogenesis is increased by PPARγ [72]. A separate study recently showed that knockdown of either PPAR γ or G0S2 resulted in apoptotic induction in 3T3-L1 cells before terminal differentiation [61]. The lack of notable defects in the adipose development of G0S2 whole-body knockout mice [58–60], however, argues against a significant role of G0S2 in adipocyte differentiation in vivo .…”