Target Disruption of G0/G1 Switch Gene 2 Enhances Adipose Lipolysis, Alters Hepatic Energy Balance, and Alleviates High Fat Diet-Induced Liver Steatosis
- Xiaodong Zhang1,3,
- Xitao Xie1,3,
- Bradlee L. Heckmann1,3,4,
- Alicia M. Saarinen1,3,
- Traci A. Czyzyk2,3 and
- Jun Liu1,3,#
- 1From Department of Biochemistry and Molecular Biology
- 2Department of Physiology and Biomedical Engineering
- 3HEALth Program, Mayo Clinic in Arizona, Scottsdale, Arizona 85259, USA
- 4Mayo Graduate School, Rochester, Minnesota 55905, USA.
- #Corresponding Author: Jun Liu, E-mail:
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 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 resistance to 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 being a contributor to obesity-associated liver steatosis.
- Received September 13, 2013.
- Accepted October 30, 2013.
- © 2013 by the American Diabetes Association.
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