Hepatic G0S2 Exacerbates Hepatic Insulin Resistance in Estrogen-Deficient Female Wistar Rats

Abstract

While it has been reported that G0/G1 switch gene 2 (G0S2) inhibited the lipolytic activity of adipose triglyceride lipase, previously, we demonstrated that hepatic G0S2 promotes hepatic insulin resistance by the exacerbation of hepatic steatosis in the high fat diet (HF) fed male Wistar rats. However, the physiological role of hepatic G0S2 is still unknown. Estrogen suppresses gluconeogenesis and de novo lipogenesis in the liver and a decrease in serum estrogen levels in menopause is closely associated with the insulin resistance. These findings indicated that postmenopausal hepatic steatosis and insulin resistance are strongly associated with reductions in estrogen levels. To investigate the involvement of hepatic G0S2 in postmenopausal insulin resistance, we studied the effect of G0S2 on insulin sensitivity in HF-fed ovariectomized female Wistar rats by overexpressing G0S2 protein using an adenovirus (Ad). Six weeks female Wistar rats were ovariectomized (OVX) or sham operated (OVI), and maintained on 60% HF for a total of 8 weeks. Ad-G0S2 or control Ad-GFP were injected to these rats after 7 weeks diet challenge. On day 7 post Ad injection, euglycemic-hyperinsulinemic clamp studies were performed after a 12-hour fast. During the clamp studies on the OVI rats, the glucose infusion rate (Ginf), the insulin stimulated glucose disposal rate (IS-GDR), and the insulin suppression of HGO were not significantly different between the G0S2 and GFP groups. On the other hand, the OVX-G0S2 rats exhibited increased clamp HGO (∼36%) and decreased suppression of HGO (∼43%) but no significant change in ISGDR compared to OVX-GFP rats. Consist with the clamp data, the insulin-stimulated phosphorylation of Akt was significantly decreased only in the liver of OVX-G0S2 rats. In conclusion, hepatic G0S2 exacerbates hepatic insulin resistance only in the estrogen deficient status. The expression level of hepatic G0S2 could affect the development of hepatic insulin resistance in the postmenopausal stage. Disclosure H. Satoh: None. Y. Sugaya: None. C.T. Moriya: None. T. Miyatsuka: Research Support; Self; Eli Lilly and Company, Japan Society for the Promotion of Science, Daiichi Sankyo Company, Limited, Novartis Pharma K.K., Astellas Pharma Inc., MSD K.K., Takeda Pharmaceutical Company Limited. H. Watada: Advisory Panel; Self; AstraZeneca. Consultant; Self; Astellas Pharma US, Inc., AstraZeneca, Boehringer Ingelheim GmbH, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Novartis AG, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Takeda Development Center Asia, Pte. Ltd.. Research Support; Self; Abbott, Astellas Pharma US, Inc., AstraZeneca, Bayer AG, Benefit One Health Care Co., Ltd., Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Johnson & Johnson Diabetes Institute, LLC., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nitto Boseki Co., Ltd., Novartis AG, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Pfizer Inc., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Terumo Medical Corporation.