Effects of Roux-en-Y gastric bypass on energy and glucose homeostasis are preserved in two mouse models of functional glucagon-like peptide-1 deficiency.

Roux - en - Y 胃旁路术对能量和葡萄糖稳态的影响在两种功能性胰高血糖素样肽 - 1 缺乏的小鼠模型中得以保留。

• 影响指数: 8.568
• 发表时间: Apr 2014
• 来源期刊: Mol Metab
• DOI: 10.1016/j.molmet.2013.11.010
• PMID: 24634822
• 文章类型: Journal Article
• 中科院分区: Q3
• 方向: 医学
• 作者列表: Mokadem M,Zechner JF,Margolskee RF,Drucker DJ,Aguirre V

关键词: GLP-1, glucagon-like peptide-1; GLP-1R, glucagon-like peptide-1 receptor; Glp1r−/−, glucagon-like peptide-1 receptor deficient mice; Gut hormones; HOMA-IR, Homeostasis Model Assessment-Insulin Resistance; Mouse model; PF-sham, pair-fed sham; RYGB, Roux-en-Y gastric bypass; Taste perception; WM-sham, weight-matched sham; WT, wild-type; Weight-loss surgery; α-Gust−/−, α-gustducin deficient mice

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。