title: Targeted disruption of G0/G1 switch gene 2 enhances adipose lipolysis, alters hepatic energy balance, and alleviates high-fat diet-induced liver steatosis.
abstract: Recent biochemical and cell-based studies identified G0/G1 switch gene 2 (G0S2) as an inhibitor of adipose triglyceride lipase (ATGL), a key mediator of intracellular triacylglycerol (TG) mobilization. Here, we show that upon fasting, G0S2 protein expression exhibits an increase in liver and a decrease in adipose tissue. Global knockout of G0S2 in mice enhanced adipose lipolysis and attenuated gain of body weight and adiposity. More strikingly, G0S2 knockout mice displayed a drastic decrease in hepatic TG content and were resistant to high-fat diet (HFD)-induced liver steatosis, both of which were reproduced by liver-specific G0S2 knockdown. Mice with hepatic G0S2 knockdown also showed increased ketogenesis, accelerated gluconeogenesis, and decelerated glycogenolysis. Conversely, overexpression of G0S2 inhibited fatty acid oxidation in mouse primary hepatocytes and caused sustained steatosis in liver accompanied by deficient TG clearance during the fasting-refeeding transition. In response to HFD, there was a profound increase in hepatic G0S2 expression in the fed state. Global and hepatic ablation of G0S2 both led to improved insulin sensitivity in HFD-fed mice. Our findings implicate a physiological role for G0S2 in the control of adaptive energy response to fasting and as a contributor to obesity-associated liver steatosis.
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic in Arizona, Scottsdale, AZ.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhang
authors.forename: Xitao
authors.initials: X
authors.lastname: Xie
authors.forename: Bradlee L
authors.initials: BL
authors.lastname: Heckmann
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Saarinen
authors.forename: Traci A
authors.initials: TA
authors.lastname: Czyzyk
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D050154:Adiposity; D000818:Animals; D018797:Cell Cycle Proteins / Q000502:physiology*; D059305:Diet, High-Fat; D004734:Energy Metabolism; D005215:Fasting / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology*; D005260:Female; D007333:Insulin Resistance; D008066:Lipolysis; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D014280:Triglycerides / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C508072:G0S2 protein, mouse; D014280:Triglycerides