Abstract:
Glucagon-like peptide-1 (GLP-1) secretion is greatly enhanced after Roux-en-Y gastric bypass (RYGB). While intact GLP-1exerts its metabolic effects via the classical GLP-1 receptor (GLP-1R), proteolytic processing of circulating GLP-1 yields metabolites such as GLP-1(9-36)amide/GLP-1(28-36)amide, that exert similar effects independent of the classical GLP-1R. We investigated the hypothesis that GLP-1, acting via these metabolites or through its known receptor, is required for the beneficial effects of RYGB using two models of functional GLP-1 deficiency - α-gustducin-deficient (α-Gust (-/-)) mice, which exhibit attenuated nutrient-stimulated GLP-1 secretion, and GLP-1R-deficient mice. We show that the effect of RYGB to enhance glucose-stimulated GLP-1 secretion was greatly attenuated in α-Gust (-/-) mice. In both genetic models, RYGB reduced body weight and improved glucose homeostasis to levels observed in lean control mice. Therefore, GLP-1, acting through its classical GLP-1R or its bioactive metabolites, does not seem to be involved in the effects of RYGB on body weight and glucose homeostasis.
摘要:
在Roux-en-Y胃旁路术(RYGB)后,胰高血糖素样肽-1(GLP-1)的分泌大大增强。虽然完整的GLP-1通过经典的GLP-1受体(GLP-1R)发挥其代谢作用,循环GLP-1的蛋白水解过程产生代谢产物如GLP-1(9-36)酰胺/GLP-1(28-36)酰胺,独立于经典GLP-1R发挥类似作用。我们研究了GLP-1通过这些代谢物或通过其已知受体起作用的假设,使用两种功能性GLP-1缺乏-α-gustagin缺陷(α-Gust(-/-))小鼠模型对RYGB的有益作用是必需的,表现出减弱的营养刺激的GLP-1分泌,和GLP-1R缺陷小鼠。我们表明,RYGB增强葡萄糖刺激的GLP-1分泌的作用在α-Gust(-/-)小鼠中大大减弱。在两种遗传模型中,RYGB降低体重并改善葡萄糖稳态至瘦对照小鼠中观察到的水平。因此,GLP-1通过其经典的GLP-1R或其生物活性代谢产物发挥作用,似乎与RYGB对体重和葡萄糖稳态的影响无关。