摘要
目的:探讨降糖药物胰高血糖素样肽1(GLP-1)受体激动剂艾塞那肽(Exe)对肥胖的ob/ob小鼠骨骼肌脂质沉积的作用及相关机制。方法:将8周龄雄性ob/ob小鼠随机分为生理盐水对照组(ob/ob组)和给药组(ob/ob+Exe组),另以野生型(WT)小鼠为WT对照组(WT组)。对ob/ob+Exe组小鼠腹腔注射Exe(24 nmol·kg−1·d−1)4周,而对WT组及ob/ob组小鼠腹腔注射等体积生理盐水4周,定期监测干预后小鼠的体重、空腹血糖(FBG)及体脂含量。用油红O染色观察骨骼肌脂质沉积情况;用ELISA进行血清中甘油三酯(TG)、游离脂肪酸(FFA)和总胆固醇及骨骼肌TG定量检测;Western blot检测腺苷酸活化蛋白激酶(AMPK)及脂代谢相关蛋白的表达情况。采用小鼠C2C12成肌细胞进行体外细胞实验,棕榈酸钠(300μmol/L)或Exe(20 nmol/L)干预24 h后,通过油红O染色及细胞内TG定量观察细胞内脂质沉积情况;Western blot法观察AMPK及脂代谢相关蛋白的表达情况;通过葡萄糖摄取实验观察细胞的葡萄糖摄取能力。结果:与ob/ob组相比,Exe治疗对小鼠的体重、FBG、体脂含量及能量摄入无显著影响(P>0.05),但可显著降低血清中FFA含量(P<0.05)。油红O染色及TG定量结果显示,Exe明显缓解ob/ob小鼠骨骼肌中的脂质沉积(P<0.05)。Western blot结果显示,Exe可降低ob/ob小鼠骨骼肌中脂质合成相关蛋白的表达水平,增加磷酸化AMPK(p-AMPK)和脂质分解相关蛋白的水平(P<0.05)。Exe显著缓解棕榈酸钠诱导的C2C12细胞脂质沉积(P<0.05),显著升高p-AMPK、脂质分解相关蛋白和葡萄糖转运蛋白4的水平,降低脂质合成相关蛋白的水平(P<0.05),并且增强细胞的葡萄糖摄取能力(P<0.05)。结论:GLP-1受体激动剂Exe可以缓解ob/ob小鼠骨骼肌中的脂质沉积,其作用可能与抑制脂质合成和促进脂质分解相关,且该作用不依赖于体重的下降。
AIM:To investigate the alleviating effect of exenatide(Exe),a glucagon-like peptide-1(GLP-1)receptor agonist,on the ectopic lipid accumulation in skeletal muscle of ob/ob mice and its mechanism.METHODS:Eight-week-old male ob/ob mice and their wild-type(WT)littermates were randomly divided into 3 groups,ob/ob group,ob/ob+Exe group and WT group,and treated with Exe at 24 nmol/kg or the same volume of saline intraperitoneally once daily for 4 weeks.The body weight,fasting blood glucose(FBG)and fat content were measured after the 4-week treat⁃ment.The oil red O staining and the quantification of triglyceride(TG)were performed on the skeletal muscle.The serum levels of TG,total cholesterol and free fatty acid(FFA)were also measured by ELISA.The expression levels of AMP-acti⁃vated protein kinase(AMPK)and lipid metabolism-related proteins were determined by Western blot.Mouse myoblast C2C12 cells were used as an in vitro model to further investigate the effects of Exe.RESULTS:As compared with the ob/ob mice treated with saline,4-week Exe treatment did not reduce body weight,FBG,food intake and fat content in ob/ob mice(P>0.05).However,serum FFA was decreased(P<0.05).Oil red O staining and the quantification of TG showed that 4-week Exe treatment significantly attenuated the ectopic lipid accumulation in the skeletal muscle of ob/ob mice(P<0.05).The results of Western blot showed that the levels of phosphorylated AMPK(p-AMPK)and lipolysis-related pro⁃teins were up-regulated,while the lipid synthesis-related proteins were down-regulated by Exe(P<0.05).Treatment with Exe alleviated the lipid accumulation in the C2C12 cells induced by sodium palmate(P<0.05),and the effects of Exe on the levels of p-AMPK and lipid metabolism-related proteins in the C2C12 cells were consistent with those in the ob/ob mice(P<0.05).Treatment with Exe also up-regulated the protein expression of glucose transporter 4 and improved the ability of glucose uptake in the C2C12 cells(P<0.05).CONCLUSION:Short-term Exe treatment attenuates the ecto
作者
郭婉蓉
陈宗兰
曹欢易
邓洪容
蔡梦茵
梁华
徐芬
GUO Wan-rong;CHEN Zong-lan;CAO Huan-yi;DENG Hong-rong;CAI Meng-yin;LIANG Hua;XU Fen(The Third Affiliated Hospital of Sun Yat sen University,Guangdong Key Laboratory of Diabetes Prevention and Treatment,Guangzhou 510630,China)
出处
《中国病理生理杂志》
CAS
CSCD
北大核心
2020年第11期1921-1927,共7页
Chinese Journal of Pathophysiology
基金
国家自然科学基金资助项目(No.81970741
No.81670782)
国家自然科学基金青年科学基金资助项目(No.81300705)
“广东特支计划”科技青年拔尖人才(No.2016TQ03R590)
广州市科技计划珠江新星专项(No.201610010175)
中央高校基本业务费青年教师重点培育项目(No.16ykzd12)。
关键词
胰高血糖素样肽1
艾塞那肽
骨骼肌
脂质
体重
Glucagon-like peptide-1
Exenatide
Skeletal muscle
Lipids
Body weight
