胰升糖素样肽1对肥胖大鼠肝脏组织中Sesn2/AMPK/mTOR信号通路的干预效应

Effect of glucagon-like peptide 1 on Sesn2/AMPK/mTOR signaling pathway in liver of obese rats induced by high-fat diet

目的:研究胰升糖素样肽1受体激动剂利拉鲁肽对肥胖大鼠肝脏组织Sesn2/AMPK/mTOR信号通路的影响。方法:雄性SD大鼠随机分为正常饮食组(NC组)与高脂饮食组(HF组),喂养12周后,每组取5只评估肥胖大鼠模型建立。HF组再随机分为HF组、低剂量利拉鲁肽组(LG组)、中剂量利拉鲁肽组(MG组)与高剂量利拉鲁肽组(HG组),各组分别给予生理盐水及不同剂量利拉鲁肽(50、100和200μg/kg,皮下注射,每天2次) 4周。16周时测定体重及附睾脂肪指数;取大鼠肝脏组织HE染色观察肝脏脂肪变性情况; Western blot法检测肝脏组织中Sesn2、AMPK、p-AMPK、mTOR和p-mTOR的蛋白水平。结果:HF组大鼠的体重明显高于NC组(P <0. 01)。HF组肝脏细胞出现脂肪变性。与NC组相比,HF组的Sesn2蛋白水平明显降低(P <0. 01),p-AMPK/AMPK水平明显降低(P <0. 01),而p-mTOR/mTOR水平与NC组相比差异没有统计学显著性。利拉鲁肽干预4周后,药物处理组大鼠体重明显低于HF组(P <0. 01),MG与HG组大鼠的附睾脂肪指数较HF组降低(P <0. 01),肝组织脂肪变性较HF组减轻; HG组的Sesn2蛋白水平明显高于HF组(P <0. 01),MG与HG组的p-AMPK/AMPK水平较HF组明显升高(P <0. 01),LG组、MG与HG组p-mTOR/mTOR水平较HF组明显降低(P <0. 01)。结论:胰升糖素样肽1受体激动剂可能通过Sesn2/AMPK/mTOR信号通路影响机体能量代谢,改善肥胖状态。

AIM: To explored the effect of glucagon-like peptide 1 receptor agonist liraglutide on Sesn2/AMPK/mTOR signaling pathway in the liver of obese rats. METHODS: Male SD rats were divided into normal chow( NC) group( n = 12) and high-fat diet( HF) group( n = 33). After 12 weeks,5 rats of each group were used to assess establishment of obese rat model. The rats in HF group were divided into 4 subgroups,HF group,low dose of liraglutide( LG) group,middle dose of liraglutide( MG) group,and high dose of liraglutide( HG) group,and treated with various doses of liraglutide( 0,50,100 and 200 μg/kg) via hypodermic injection twice a day for 4 weeks. The body weight and epididymal fat index of the rats at the 16 th week were measured. The liver tissue fatty degeneration was observed. The protein levels of Sesn2,AMPK,p-AMPK,mTOR and p-mTOR were determined by Western blot. RESULTS: The body weight of rats in HF group was obviously higher than that in NC group( P < 0. 01). Compared with NC group,the levels of Sesn2 and p-AMPK/AMPK were significantly decreased in HF group( P < 0. 01),while the level of p-mTOR/mTOR was not changed. After treatment with liraglutide for 4-week,the body weight of the rats in LG,MG and HG groups was obviously lower than that in HF group( P < 0. 01),and epididymal fat index of the rats in MG and HG groups was obviously lower than that in HF group( P < 0. 01). The protein level of Sesn2 in HG group was obviously higher than that in HF group( P < 0. 01). The level of p-AMPK/AMPK was significantly increased in MG and HG groups( P < 0. 01). The level of p-mTOR/mTOR was significantly increased decreased in LG,MG and HG groups( P < 0. 01). CONCLUSION: Glucagon-like peptide 1 receptor agonist liraglutide affects energy metabolism and improves the state of obesity through Sesn2/AMPK/mTOR signaling pathway.