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

Mol Metab. 2013 Dec 11;3(2):191-201. doi: 10.1016/j.molmet.2013.11.010. eCollection 2014 Apr.


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.

Keywords: 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.