Targeted disruption of G0/G1 switch gene 2 enhances adipose lipolysis, alters hepatic energy balance, and alleviates high-fat diet-induced liver steatosis

Xiaodong Zhang, Xitao Xie, Bradlee L. Heckmann, Alicia M. Saarinen, Traci A. Czyzyk, Jun D Liu

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Recent biochemical and cell-based studies identified G0/G 1 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.

Original languageEnglish (US)
Pages (from-to)934-946
Number of pages13
JournalDiabetes
Volume63
Issue number3
DOIs
StatePublished - Mar 2014

Fingerprint

Switch Genes
Lipolysis
High Fat Diet
Fatty Liver
Liver
Gene Knockdown Techniques
Fasting
Triglycerides
Glycogenolysis
Gene Knockout Techniques
Gluconeogenesis
Adiposity
Lipase
Knockout Mice
Insulin Resistance
Adipose Tissue
Hepatocytes
Fatty Acids
Obesity
Body Weight

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Targeted disruption of G0/G1 switch gene 2 enhances adipose lipolysis, alters hepatic energy balance, and alleviates high-fat diet-induced liver steatosis. / Zhang, Xiaodong; Xie, Xitao; Heckmann, Bradlee L.; Saarinen, Alicia M.; Czyzyk, Traci A.; Liu, Jun D.

In: Diabetes, Vol. 63, No. 3, 03.2014, p. 934-946.

Research output: Contribution to journalArticle

Zhang, Xiaodong ; Xie, Xitao ; Heckmann, Bradlee L. ; Saarinen, Alicia M. ; Czyzyk, Traci A. ; Liu, Jun D. / Targeted disruption of G0/G1 switch gene 2 enhances adipose lipolysis, alters hepatic energy balance, and alleviates high-fat diet-induced liver steatosis. In: Diabetes. 2014 ; Vol. 63, No. 3. pp. 934-946.
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