应用神经肽YY5受体反义基因治疗肥胖大鼠高leptin血症效果的探讨

Efficacy of Antisense Oligodeoxynucleotide of Neuropeptide Y Y5 Receptor in Treating Hyperleptinemia by Intracerebral Ventricular Administration in Diet-induced Obese Rats

目的:探讨神经肽YY5(NPYY5)受体反义基因治疗对肥胖大鼠高leptin血症的改善作用及其机制。方法:建立高营养饮食诱导的肥胖大鼠模型,侧脑室插管后注射NPYY5受体反义、正义、错义寡核苷酸或生理盐水,观察大鼠腹膜后与生殖器周围脂肪组织湿重的变化,并采用ELISA双抗体夹心法测定血清leptin水平、放免法测定血清胰岛素水平。结果:①高营养饮食诱导的肥胖模型大鼠血清leptin水平、血清胰岛素水平及两部位脂肪组织湿重明显高于正常大鼠;②经NPYY5受体反义寡核苷酸干预后,肥胖大鼠血清leptin水平、血清胰岛素水平、腹膜后脂肪组织湿重均明显降低,但生殖器周围脂肪组织湿重无明显变化;③大鼠血清leptin水平、血清胰岛素水平、腹膜后脂肪组织湿重间均存在一定的正相关关系。结论:侧脑室注射NPYY5受体反义寡核苷酸可显著改善肥胖大鼠的高leptin血症,推测其机制可能与大鼠进食行为改变、腹膜后脂肪组织减少、血清胰岛素水平下降等因素有关。

Objective: To study the efficacy of antisense oligonucleotide of neuropeptide Y (NPY) Y5 receptor in treating hyperleptinemia by intracerebral ventricular administration in diet induced obese rats. Methods: The obese rats were prepared by feeding a high nutritive diet for 7 weeks. The lateral ventricular of obese rats was cannulated. Either 10 μl / rat (5 g /L ) different neuropeptide Y Y5 receptor oligodeoxynucleotide, including antisense, sense and mismatched oligodeoxynucleotide or 10 μl saline was administered into ventricle through cannula three times per day. Two days later the rats were slaughtered. The weights of both retroperitoneal and epididymal adipose tissue were measured, and the serum insulin and leptin were detected respectively by radioimmunoassay method and the murine leptin ELISA kit. Results: 1 The level of serum leptin was significantly higher in experimental rats than that in normal rats. Similarly, the level of serum insulin and the weights of both retroperitoneal and epididymal adipose tissue were increased in experimental rats. 2 After the diet induced obese rats were intraventricularly administered with NPY Y5 receptor antisense oligodeoxynucleotide, the levels of serum leptin and insulin were significantly decreased with the reduction of weight in retroperitoneal adipose tissue. There was, however, no significant difference in the weight of epididymal adipose tissue between pre treated and post treated duration. 3 There is a significant positive correlation among the level of serum leptin, of serum insulin and the weight of retroperitoneal adipose tissue in diet induced obese rats. Conclusion: Intracerebral ventricular administration of antisense oligodeoxynucleotide of neuropeptide Y Y5 receptor may improve hyperleptinemia in diet induced obese rats and decrease the weight of retroperitoneal adipose tissue and the level of serum insulin.