肥胖大鼠模型的建立及其脂代谢相关分子机制研究

Establishment of a rat model of obesity and its lipid metabolism-related mechanisms

目的建立饮食诱导的肥胖(diet-induced obesity,DIO)大鼠模型并初步探讨其发病的分子机制。方法用脂肪含量30%的高脂饲料饲喂雄性SD大鼠25周,观察大鼠体重、Lee's指数、肝组织病理改变,检测大鼠空腹血糖及空腹血清胰岛素水平,并通过real-time PCR,检测成模大鼠肝脏中乙酰辅酶A羧化酶(ACC)、脂肪酸合酶(FAS)、激素敏感酯酶(HSL)以及固醇调节元件结合蛋白-1c(SREBP-1c)的表达变化。结果高脂饲料饲喂6周后,DIO组大鼠体重、Lee's指数均显著增加;25周后肝脏脂肪异常蓄积,出现中重度脂肪肝,空腹血糖及胰岛素水平显著升高,出现明显的胰岛素抵抗。肝脏中ACC、FAS和HSL表达显著增加,SREBP-1c表达水平达到正常组的2.56倍,两组间差异极其显著。结论成功建立了DIO大鼠模型,通过检测脂代谢相关基因的表达水平,初步阐释了营养性肥胖的发生与脂代谢变化之间的关系,SREBP-1c,ACC,FAS和HSL参与了DIO的形成,从而初步揭示了脂代谢变化与营养性肥胖的发生的关系。

Objective To establish a rat model of diet-induced obesity（DIO）,and explore its molecular mechanism.Methods Ninty 3-week old male Sprague-Dawley rats in the diet-induced obesity（DIO） experimental group were fed with high fat diet（containing 30% fat） for 25 weeks,and 20 healthy rats in the normal control group were fed with normal diet.The following indicators were evaluated： body weight,Lee＇s index,the fasting glucose and insulin levels and pathological changes in the liver tissue.The expression of acetyl-CoA carboxylase（ACC）,fatty acid synthetase（FAS）,hormone-sensitive lipase（HSL）,which are key enzymes in lipid metabolism,and the transcription factor sterol regulatory element binding protein-1c（SREBP-1c） was analyzed by real-time PCR.Results DIO rat models were successfully produced by high fat diet for 25 weeks.Compared with the normal rats,after fed with high fat diet for 6 weeks,the DIO rats showed significant increase in the body weight and Lee＇s index.After high fat diet for 25 weeks,the DIO rats showed abnormal liver fat accumulation and moderate to severe fatty liver,significant increase in the fasting glucose and insulin levels,and insulin resistance.Real-time PCR results revealed that compared with the normal rats,after feeding with high fat diet for 25 weeks,the expression of ACC,FAS,HSL and the transcription factor SREBP-1c were increased significantly in the liver of DIO rats.The expression of SREBP-1c in the liver of DIO rats was 2.56-fold higher than that of the normal rats.Conclusions We have successfully induced normal SD rats to develop diet-induced obesity by feeding high fat diet for 25 weeks.The expressions of lipid metabolism genes SREBP-1c,ACC,FAS and HSL are all involved in the development of DIO,providing an explaination to the relationship between the changes in hepatic lipid metabolism and the development of obesity.