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目的在长期(4个月)高脂高糖饮食诱导的胰岛素抵抗小鼠模型上,评价过氧化物酶体增殖物激活受体β(PPARβ)亚型激动剂GW501516对胰岛素抵抗的改善作用,并对可能的相关机制进行探讨。方法C57BL/6J小鼠采用高脂高糖饮食(35%脂肪,30%麦芽糖)诱导4个月,待产生明显的糖脂代谢紊乱。实验分为正常对照、饮食导致的肥胖(DIO)模型与DIO模型+GW501516(10mg·kg-1·d-1)给药组。隔天监测体重与进食量情况,以葡萄糖氧化酶法检测血糖,并进行口服葡萄糖耐量试验和血脂(甘油三酯、总胆固醇和高密度脂蛋白)含量的检测。以组织学方法检测肝脏异位脂积聚及病理变化情况。为确证其相关作用机制,采用RT-PCR方法检测骨骼肌内PPARβ下游糖脂代谢靶基因的表达。结果GW501516有效改善模型小鼠的胰岛素抵抗,显著降低口服糖耐量曲线下面积〔DIO模型组,(32.4±4.6)mmol·h·L-1, DIO +GW501516组,(23.4±2.5)mmol·h·L-1,n=7 ~8, P<0.05〕,降低空腹血糖,增加血清高密度脂蛋白含量,减轻模型小鼠的肝脂肪变性。此外,RT-PCR结果表明,骨骼肌卡尼汀(肉碱)软脂酰转移酶1b,解偶联蛋白(UCP)2,UCP3明显上调,同时葡萄糖转运蛋白也明显上调。结论GW501516显著改善模型小鼠的胰岛素抵抗,恢复其空腹血糖值,降低肝脏内异位脂积聚,其治疗作用机制可能与①促进骨骼肌内脂肪酸氧化和能量的解偶联,②促进骨骼肌内的糖摄取有关,提示PPARβ可能是胰岛素抵抗及代谢综合征的有效治疗靶标。
Objective To evaluate the effect of peroxisome proliferator-activated receptor β (PPARβ) subtype agonist GW501516 on insulin resistance in a long-term (4 months) mouse model of insulin resistance induced by high-fat and high-sugar diet. Discuss possible related mechanisms. Methods C57BL / 6J mice were induced with high-fat and high-carbohydrate diet (35% fat and 30% maltose) for 4 months, and obvious dyslipidemia was observed. The experiment was divided into normal control, diet-induced obesity (DIO) model and DIO model + GW501516 (10 mg · kg-1 · d-1) administered group. The body weight and food intake were monitored on the next day. Blood glucose was measured by glucose oxidase method, and oral glucose tolerance test and blood lipid (triglyceride, total cholesterol and high density lipoprotein) contents were measured. Histological examination of liver ectopic fat accumulation and pathological changes. To confirm its mechanism of action, RT-PCR was used to detect the expression of target genes of glycolipid metabolism downstream of PPARβ in skeletal muscle. Results GW501516 effectively improved insulin resistance in model mice and significantly decreased the area under the oral glucose tolerance curve (DIO model group, (32.4 ± 4.6) mmol · h · L -1, DIO + GW501516 group, (23.4 ± 2.5) mmol · h · L-1, n = 7 ~ 8, P <0.05〕, lower fasting blood glucose, increase serum high-density lipoprotein and alleviate hepatic steatosis in model mice. In addition, the results of RT-PCR showed that the carnitine (carnitine) palmitoyltransferase 1b, uncoupling protein (UCP) 2 and UCP3 in skeletal muscle were significantly up-regulated and the glucose transporter was also significantly up-regulated. Conclusion GW501516 can significantly improve insulin resistance, restore fasting blood glucose and decrease hepatic ectopic fat accumulation in model mice. The mechanism may be related to: (1) promoting uncoupling of oxidative and energy metabolism of skeletal muscle; (2) Suggestive of PPARβ may be an effective therapeutic target of insulin resistance and metabolic syndrome.