VPAC1激动剂的抗肥胖作用(英文)

In vivo anti-obesity effect of the agonist for receptor VPAC1

VPAC1是垂体腺苷酸环化酶激活多肽(pituitary adenylate cyclase-activating polypeptide,PACAP)和血管活性肠肽(vasoactive intestinal polypeptide,VIP)的共同受体。VPAC1介导PACAP和VIP抑制食欲和抗炎的生物学功能。本研究体外实验表明,VPAC1在分化成熟的3T3-L1脂肪细胞中表达增高,并且VPAC1激动剂(10～1000nmol/L每1×106cells)可诱导脂肪细胞脂解,因此我们预计VPAC1激动剂具有抗肥胖及肥胖综合征的作用。为研究VAPC1激动剂[Lys15,Arg16,Leu27]-VIP(1-7)GRF(8-27)对营养性肥胖及肥胖综合征的干预作用,本研究又设计了两组体内实验:(1)高脂喂养NIH雄性小鼠4周,同时腹腔注射VPAC1激动剂;以注射生理盐水作为对照;(2)高脂喂养NIH雄性小鼠5周,构建肥胖模型后,再腹腔注射VPAC1激动剂4周,同样以注射生理盐水作为对照。采集摄食、体重、体脂、血糖及血脂等指标。结果显示,VPAC1激动剂显著抑制摄食、抑制高脂饮食诱导的体重及体脂(附睾及背部)重量的增长,并有效改善高脂饮食诱导的高血糖及高血脂,提高机体的糖耐受。高剂量(每天50nmol/kg体重)VPAC1激动剂比低剂量(每天5nmol/kg体重)有更显著的抗肥胖作用,提示VPAC1激动剂的抗肥胖作用具有剂量依赖性。以上结果表明,VPAC1激动剂不仅能抑制高脂诱导的肥胖的发展,而且可有效改善肥胖相关疾病;其抗肥胖作用的机制是复杂整合的,值得进一步深入研究。

It was hypothesized that the VPAC1 agonist may exert anti-obesity functions because VPAC1 is involved in the anorexigenic effects and the anti-inflammatory function of pituitary adenylate cyclase-activating polypeptide （PACAP）/vasoactive intestinal polypeptide （VIP）. Furthermore, our in vitro test showed that the expression of VPAC1 increased significantly after the 3T3-L1 adipocytes were differentiated, and that incubation of adipocytes with VPAC1 agonist （10-1 000 nmol/L per Ix 106 cells） resulted in stimulation of lipolysis. To test the effect of VPAC1 agonist [Lysl5, Argl6, Leu27]-VIP （1-7） GRF （8-27） on diet-induced obesity （DIO）, we further designed the following two in vivo experiments： （1） Mice were fed on high-fat diet （HFD） and intraperitoneally （i.p.） treated with VPAC1 agonist simultaneously for 28 d; （2） Mice were given HFD for 35 d, and subsequently fed on the same HFD and i.p. treated with VPAC 1 agonist for the next 28 d. The physiological indices, including body weight, weight of white adipose tissue, plasma glucose and blood lipid, were collected. The results showed that treatment with VPAC1 agonist inhibited ingestion significantly and prevented the elevations in body weight and the weights of the white adipose tissues （epididymal and dorsal） induced by HFD. The increases in plasma glucose, cholesterol, triglycerides and LDL induced by HFD were also down-regulated in mice treated with VPAC1 agonist. VPAC1 agonist treatment also improved the glucose tolerance. Therefore, VPAC1 agonist treatment inhibits the development of the obesity induced by HFD and helps to improve the morbidities associated with DIO.