细胞因子信号转导抑制因子3表达下调抵抗高脂饮食诱导肥胖的作用机制研究

Down-regulation of suppressor of cytokine signaling 3 expression in hypothalamus attenuates high-fat dietinduced obesity in rats

目的 探讨RNA干扰下丘脑弓状核细胞因子信号转导抑制因子3（SOCS3）对饮食诱导大鼠肥胖的防治作用。方法利用慢病毒介导的RNA干扰技术建立大鼠下丘脑弓状核SOCS3基因沉默的动物模型，然后给予高脂饲料喂养8周处死，采用放射免疫法测定血清瘦素和胰岛素的含量。免疫组化及实时定量PCR方法检测大鼠下丘脑注射部位SOCS3的表达。结果干扰组大鼠下丘脑注射部位的SOCS3蛋白表达明显降低，SOCS3rnRNA表达量下调49％（P〈0．01），干扰组大鼠体重增长缓慢．血清瘦素[（8．18±2．10对10．85±2．23）ng／m1]、胰岛素[（18．89±4．88对26．78±6．01）mU／L]、血糖[（4．89±0．91对6．26±1．41）mmol／L]及甘油三酯[（0．47±0．10对0．62±0．16）mmol／L]水平均明显降低（P〈0．05或P〈0．01）。结论利用RNA干扰下调下丘脑弓状核SOCS3基因的表达能够抵抗高脂饮食诱导的肥胖、改善瘦素抵抗和相关的代谢紊乱。

Objective To investigate whether hypothalamic silencing of suppressor of cytokine signaling 3 （ SOCS3 ） by RNA interference （ RNAi ） attenuates diet-induced obesity and leptin resistance in rats. Methods Hypothalamic SOCS3-deficient rats were established by means of lentiviral vector （LV） mediated RNAi technique, and then were fed with a high-fat diet for 8 weeks. After the rats were sacrificed, the serum leptin and insulin concentrations were measured by RIA, and the expression of SOCS3 in hypothalamus was detected by immnnohistochemistry and reahime PCR. Results The immunostaining showed that SOCS3 protein expression was significantly reduced and the expression of SOCS3 mRNA was decreased by 49% in SOCS3 RNAi group compared to the controls（P〈0.01 ）. The rats with hypothalamic SOCS3 knockdown exhibited a significant hampering in gaining body weight with lowered concentrations of leptin[ （8.18±2. 10 vs 10.85±2.23） ng/ml] , insulin （ 18.89±4.88 vs 26.78±6.01 ） mU/L ], glucose [ （4.89±0.91 vs 6.26±1.41 ） mmol/L ] and triglyceride [ （0.47± 0.10 vs 0. 62-＋ 0.16） mmol/L when exposed to a high-fat diet（P〈0.05 or P〈0.01 ）. Conclusion The results provide evidence that rats with hypothalamic SOCS3 silencing by RNAi are resistant to diet-induced obesity, leptin resistance, and metabolic disorder.