成纤维细胞生长因子21通过抑制肥胖小鼠肝脏氧化应激改善胰岛素抵抗

Fibroblast growth factor 21 improves insulin resistance via inhibiting hepatic oxidative stress in obese mice

目的探索成纤维细胞生长因子21(FGF21)改善胰岛素抵抗的可能机制以及在氧化应激过程中的作用。方法构建高脂饮食小鼠模型后分组,干预组小鼠注射FGF21,进行糖耐量及胰岛素耐量实验测定,运用免疫印迹分析和免疫共沉淀检测肝脏组织氧化应激标志物(iNOS)和胰岛素信号通路分子的蛋白(IRS-1和Akt)表达情况,同时运用油红O染色评估肝脂肪变性水平。结果与模型组比较,FGF21干预组的体重、血糖及胰岛素水平降低,胰岛素敏感性提高。同时,在FGF21干预组小鼠肝脏组织的iNOS及TNF-α蛋白表达降低,IRS-1酪氨酸和Akt丝氨酸的磷酸化水平增高;FGF21组较对照组的肝脏脂质积聚明显减少,改善了肥胖小鼠的肝脂肪变性。结论 FGF21可作为一个重要的糖脂代谢调控子,通过抑制肝脏氧化应激,重建其受损的胰岛素信号通路,减少肝脏脂肪积聚,改善肥胖小鼠的胰岛素抵抗,具有潜在的临床应用价值。

Objective To explore the mechanism of insulin resistance regulated by fibroblast growth factor 21（FGF21）and identify its role in oxidative stress.Methods High-fat diet-induced obese mice were treated with FGF21,and hepatic oxidative stress markers such as iNOS and insulin signaling molecules such as IRS-1 and Akt were assessed by Western blot and co-immunoprecipitation.Meanwhile,liver steatosis was assessed in liver sections stained with oil red O.Results Obese mice in FGF21 group showed reduced body weight,blood glucose and serum insulin levels,and improved insulin sensitivity as measured by glucose tolerance testing（GTT）and insulin tolerance testing（ITT）compared with obese mice in vehicle group.Meanwhile,FGF21 treatment in obese mice decreased protein expressions of iNOS and TNF-α,and increased insulin-stimulated IRS-1 tyrosine phosphorylation and Akt Ser-473 phosphorylation,indicating that FGF21 inhibited hepatic oxidative stress and restored impaired insulin signaling.Additionally,we found significantly reduced lipid accumulation in liver sections stained with oil red O in FGF21-treated obese mice.Conclusion Our results support the notion that FGF21 is an important regulator of insulin resistance and that FGF21 may reduce lipid accumulation in the liver,restore hepatic insulin signaling and improve insulin sensitivity in obese mice,at least in part,by inhibiting hepatic oxidative stress.Therefore,FGF21 has a potential value in clinical application.