title: Peripheral, but not central, GLP-1 receptor signaling is required for improvement in glucose tolerance after Roux-en-Y gastric bypass in mice.
abstract: Roux-en-Y gastric bypass (RYGB) causes profound weight loss and remission of diabetes by influencing metabolic physiology, yet the mechanisms behind these clinical improvements remain undefined. After RYGB, levels of glucagon-like peptide-1 (GLP-1), a hormone that enhances insulin secretion and promotes satiation, are substantially elevated. Because GLP-1 signals in both the periphery and the brain to influence energy balance and glucose regulation, we aimed to determine the relative requirements of these systems to weight loss and improved glucose tolerance following RYGB surgery in mice. By pharmacologically blocking peripheral or central GLP-1R signaling, we examined whether GLP-1 action is necessary for the metabolic improvements observed after RYGB. Diet-induced obese mice underwent RYGB or sham operation and were implanted with osmotic pumps delivering the GLP-1R antagonist exendin-(9-39) (2 pmol·kg(-1)·min(-1) peripherally; 0.5 pmol·kg(-1)·min(-1) centrally) for up to 10 wk. Blockade of peripheral GLP-1R signaling partially reversed the improvement in glucose tolerance after RYGB. In contrast, fasting glucose and insulin sensitivity, as well as body weight, were unaffected by GLP-1R antagonism. Central GLP-1R signaling did not appear to be required for any of the metabolic improvements seen after this operation. Collectively, these results suggest a detectable but only modest role for GLP-1 in mediating the effects of RYGB and that this role is limited to its well-described action on glucose regulation.
authors.affiliation: Obesity, Metabolism, and Nutrition Institute and Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; and.
authors.forename: Jill S
authors.initials: JS
authors.lastname: Carmody
authors.affiliation: Obesity, Metabolism, and Nutrition Institute and Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; and Departamento de Cirugia Digestiva, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Muñoz
authors.affiliation: Obesity, Metabolism, and Nutrition Institute and Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; and.
authors.forename: Huali
authors.initials: H
authors.lastname: Yin
authors.affiliation: Obesity, Metabolism, and Nutrition Institute and Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; and LMKaplan@partners.org.
authors.forename: Lee M
authors.initials: LM
authors.lastname: Kaplan
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D001835:Body Weight; D059305:Diet, High-Fat; D004734:Energy Metabolism; D015390:Gastric Bypass; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D009765:Obesity / Q000378:metabolism* / Q000601:surgery; D010446:Peptide Fragments / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D001786:Blood Glucose; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D010446:Peptide Fragments; C083773:exendin (9-39); D052216:Glucagon-Like Peptide 1
keywords: Roux-en-Y gastric bypass; central regulation; glucagon-like peptide-1; glucose tolerance; obesity