Liver‐specific G0/G1 switch gene 2 (G0s2) expression promotes hepatic insulin resistance by exacerbating hepatic steatosis in male Wistar rats

Background Hepatic steatosis is strongly associated with insulin resistance. It has been reported that G0 /G1 switch gene 2 (G0s2) inhibits the lipolytic activity of adipose triglyceride lipase, which is a major lipase in the liver as well as in adipocytes. Moreover, G0s2 protein content is increased in the livers of high‐fat diet (HFD)‐fed rats. In the present study, we investigated the effect of hepatic G0s2 on insulin sensitivity in male Wistar rats. Methods Male Wistar rats were fed a 60% HFD for 4 weeks. After 3 weeks of feeding, rats were injected with adenovirus‐expressing green fluorescent protein (Ad‐GFP; control) or adenovirus‐expressing mouse G0s2 (Ad‐G0s2). On Day 7 after injection, a euglycemic–hyperinsulinemic clamp study was performed in rats fasted for 8 h. Results Body weight and fasting glucose levels were not significantly different between the Ad‐GFP and Ad‐G0s2 groups. During the clamp study, the glucose infusion rate required for euglycemia decreased significantly by 16% in the Ad‐G0s2 compared with Ad‐GFP group. The insulin‐suppressed hepatic glucose output increased significantly in the Ad‐G0s2 group, but the insulin‐stimulated glucose disposal rate was not significantly different between the two groups. Consistent with the clamp data, insulin‐stimulated phosphorylation of Akt decreased significantly in livers of rats injected with Ad‐G0s2. Furthermore, Oil Red O‐staining indicated that overexpression of G0s2 protein in the liver promoted hepatic steatosis by 2.5‐fold in HFD‐fed rats. Conclusion The results of the present study indicate that hepatic G0s2 protein may promote hepatic insulin resistance by exacerbating hepatic steatosis. 背景 肝脏脂肪变性与胰岛素抵抗显著相关。既往已经有研究报告,G0/G1开关基因2(G0/G1 switch gene 2,G0s2)可以抑制脂肪组织中甘油三酯脂肪酶的脂解活性,这种酶是肝脏以及脂肪细胞中主要的脂肪酶。此外,在高脂饮食饲养的大鼠肝脏中G0s2蛋白含量增多。在当前的这项研究中,我们在雄性Wistar大鼠中探讨肝脏G0s2对胰岛素敏感性的影响。 方法 雄性Wistar大鼠使用60%的高脂饮食饲养共4周。在饲养3周后,对两组大鼠分别注射腺病毒表达的绿色荧光蛋白(adenovirus‐expressing green fluorescent protein,Ad‐GFP:对照组)或者腺病毒表达的小鼠G0s2(Ad‐G0s2)。注射后第7天,大鼠禁食8小时之后再进行正常血糖‐高胰岛素钳夹试验。 结果 Ad‐GFP组与Ad‐G0s2组之间的体重以及空腹血糖水平都没有显著性差异。在钳夹试验中,与Ad‐GFP组相比,Ad‐G0s2组维持正常血糖所需要的葡萄糖输注率显著下降了16%。在Ad‐G0s2组中胰岛素抑制后的肝脏葡萄糖输出显著增多,但是两组之间胰岛素激发的葡萄糖利用率却没有显著差异。与钳夹试验数据相一致的是,在注射Ad‐G0s2的大鼠肝脏中胰岛素激发的Akt磷酸化也显著减少了。此外,油红染色结果表明在高脂饮食饲养的大鼠肝脏中G0s2蛋白过表达导致肝脏脂肪变性增加了2.5倍。 结论 当前这项研究结果表明,肝脏G0s2蛋白可能通过加重肝脏脂肪变性从而导致肝脏胰岛素抵抗。 Lipid accumulation in liver samples from high‐fat diet‐fed rats on Day 7 after injection of adenovirus‐expressing green fluorescent protein (Ad‐GFP; control) or adenov