title: 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.
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.
authors.affiliation: Center for Hypothalamic Research, Division of Digestive and Liver Diseases, Department of Internal Medicine, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Mokadem
authors.affiliation: Center for Hypothalamic Research, Division of Digestive and Liver Diseases, Department of Internal Medicine, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.
authors.forename: Juliet F
authors.initials: JF
authors.lastname: Zechner
authors.affiliation: Monell Chemical Senses Center, 3500 Market Street, Philadelphia, PA 19104, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Margolskee
authors.affiliation: Department of Medicine, Mt. Sinai Hospital, Samuel Lunenfeld Research Institute, University of Toronto, 600 University Avenue, Toronto, Ontario, Canada M5G 1X5.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
authors.affiliation: Center for Hypothalamic Research, Division of Digestive and Liver Diseases, Department of Internal Medicine, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Aguirre
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