Sugaya Yoshiyuki, Satoh Hiroaki
Department of Nephrology, Hypertension, Diabetology, Endocrinology, and Metabolism, Fukushima Medical University, Fukushima, Japan.
J Diabetes. 2017 Aug;9(8):754-763. doi: 10.1111/1753-0407.12482. Epub 2016 Nov 14.
Hepatic steatosis is strongly associated with insulin resistance. It has been reported that G /G 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.
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.
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.
The results of the present study indicate that hepatic G0s2 protein may promote hepatic insulin resistance by exacerbating hepatic steatosis.
肝脂肪变性与胰岛素抵抗密切相关。据报道，G0/G1开关基因2（G0s2）可抑制脂肪甘油三酯脂肪酶的脂解活性，该酶是肝脏和脂肪细胞中的主要脂肪酶。此外，高脂饮食（HFD）喂养的大鼠肝脏中G0s2蛋白含量增加。在本研究中，我们调查了肝脏G0s2对雄性Wistar大鼠胰岛素敏感性的影响。
雄性Wistar大鼠喂食60%的HFD，持续4周。喂食3周后，大鼠注射表达绿色荧光蛋白的腺病毒（Ad-GFP；对照组）或表达小鼠G0s2的腺病毒（Ad-G0s2）。注射后第7天，对禁食8小时的大鼠进行正常血糖-高胰岛素钳夹试验。
Ad-GFP组和Ad-G0s2组之间的体重和空腹血糖水平无显著差异。在钳夹试验期间，与Ad-GFP组相比，Ad-G0s2组维持正常血糖所需的葡萄糖输注速率显著降低了16%。Ad-G0s2组胰岛素抑制的肝脏葡萄糖输出显著增加，但两组之间胰岛素刺激的葡萄糖处置率无显著差异。与钳夹数据一致，注射Ad-G0s2的大鼠肝脏中胰岛素刺激的Akt磷酸化显著降低。此外，油红O染色表明，在HFD喂养的大鼠中，肝脏中G0s2蛋白过表达使肝脂肪变性增加了2.5倍。
本研究结果表明，肝脏G0s2蛋白可能通过加重肝脂肪变性来促进肝脏胰岛素抵抗。
