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肥胖大鼠模型的建立及其发病的分子机制研究

发布时间:2018-05-07 07:05

  本文选题:DIO大鼠 + 脂代谢 ; 参考:《北京协和医学院》2010年硕士论文


【摘要】:饮食诱导的肥胖(Diet-induced obesity, DIO)动物模型能够较好地模拟人类肥胖的发病过程,但是DIO动物的发病机制尚未完全阐明。本研究采用雄性SD大鼠作为模型动物,通过饲喂高脂饲料成功诱导普通SD大鼠成为DIO大鼠,并通过Real-time PCR技术,研究了本模型大鼠的发病机制。 结果表明,以脂肪含量为30%的高脂饲料饲喂25周,可以诱导普通SD大鼠成为DIO大鼠,造模成功率为45%。高脂饲料饲喂25周后,DIO组大鼠体重、Lee's指数和平均体脂总重量均显著增加;肝脏脂肪异常蓄积,出现中重度脂肪肝;血清生化结果显示,本DIO模型大鼠肝肾功能未见异常,血脂正常,空腹血糖及胰岛素水平显著升高,出现明显的胰岛素抵抗。 Real-time PCR的结果显示,高脂饲料饲喂25周后,DIO组大鼠肝脏中脂肪酸合成的关键酶ACC和FAS表达量显著增加,甘油三酯水解的限速酶HSL表达显著增加;脂代谢相关酶的转录因子SREBP-1c表达水平达到正常组的2.56倍,两组间差异极其显著。 根据以上的研究结果,我们初步推测出DIO大鼠肥胖的发生与肝脂代谢相关基因及其转录调控的关系。长期高脂饲料的饲喂使SD大鼠机体发生肥胖,脂肪组织的异常增加通过多种机制诱发机体产生胰岛素抵抗,从而血清胰岛素水平代偿性增加。胰岛素激活了肝脏中SREBP-1c的转录,SREBP-1c作为转录因子激活其靶基因ACC、FAS、HSL的表达,从而使脂肪酸合成和甘油三酯水解增加,但是由于脂质的合成速度大大超过分解速度,使脂代谢发生紊乱,导致脂肪在肝组织的异常蓄积,从而出现脂肪肝。由于SREBP-1c可抑制胰岛素信号转导,使葡萄糖利用受阻,从而导致血糖逐渐升高。高血糖、胰岛素抵抗、脂肪肝与肝脂代谢紊乱又进一步加剧了肥胖的进程。 综上所述,本研究用高脂饲料饲喂SD大鼠25周,成功制作了伴有中重度脂肪肝、高血糖和胰岛素抵抗的DIO大鼠模型,并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,为深入研究营养性肥胖的发病机制奠定了基础。
[Abstract]:Diet-induced obesity (dio) animal model can well simulate the pathogenesis of human obesity, but the pathogenesis of DIO animals has not been fully elucidated. In this study, male SD rats were used as model animals. The normal SD rats were induced to become DIO rats by feeding high fat diet. The pathogenesis of the model rats was studied by Real-time PCR technique. The results showed that the normal SD rats could be induced into DIO rats after 25 weeks of feeding with 30% high fat diet. The success rate of modeling was 45.5%. After 25 weeks of feeding with high fat diet, the body weight index and average body fat total weight of rats in DIO group were significantly increased, liver fat abnormal accumulation, moderate and severe fatty liver appeared, serum biochemical results showed that there was no abnormal liver and kidney function in this DIO model rats. With normal blood lipids, fasting blood glucose and insulin levels were significantly increased and insulin resistance was observed. The results of Real-time PCR showed that the expression of ACC and FAS, the rate-limiting enzyme HSL of triglyceride hydrolysis, was significantly increased in livers of rats fed with high-fat diet for 25 weeks. The expression level of transcription factor SREBP-1c was 2.56 times higher than that of the normal group, and the difference between the two groups was very significant. Based on the above results, we preliminarily speculated the relationship between obesity and liver lipid metabolism related genes and their transcriptional regulation in DIO rats. Long-term high-fat diet could induce obesity in SD rats, and the abnormal increase of adipose tissue could induce insulin resistance through various mechanisms, thus the level of serum insulin was compensatory. Insulin activates the expression of the target gene of SREBP-1c, SREBP-1c, as a transcription factor in the liver, thus increasing fatty acid synthesis and triglyceride hydrolysis, but the rate of lipid synthesis is much faster than that of decomposition. Disorder of lipid metabolism, leading to abnormal accumulation of fat in liver tissue, thus fatty liver. Because SREBP-1c can inhibit insulin signal transduction, glucose utilization is blocked, which leads to blood glucose increasing gradually. Hyperglycemia, insulin resistance, fatty liver and liver lipid metabolism disorders further exacerbate the process of obesity. To sum up, the DIO rat model with moderate and severe fatty liver, hyperglycemia and insulin resistance was successfully made by feeding SD rats with high fat diet for 25 weeks, and the expression level of genes related to lipid metabolism was detected. The relationship between the occurrence of nutritional obesity and the changes of lipid metabolism was preliminarily explained, which laid a foundation for the further study of the pathogenesis of nutritional obesity.
【学位授予单位】:北京协和医学院
【学位级别】:硕士
【学位授予年份】:2010
【分类号】:R589.2;R-332

【参考文献】

相关期刊论文 前3条

1 陈兰亭;;单纯性肥胖症的研究进展[J];山东医药;2009年25期

2 唐韬,李燕;固醇调节元件结合蛋白与脂质代谢[J];生理科学进展;2005年01期

3 盛志峰;肥胖与胰岛素抵抗[J];医学综述;2003年07期



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