title: GLP-1 receptor signaling is not required for reduced body weight after RYGB in rodents.
abstract: Exaggerated GLP-1 and PYY secretion is thought to be a major mechanism in the reduced food intake and body weight after Roux-en-Y gastric bypass surgery. Here, we use complementary pharmacological and genetic loss-of-function approaches to test the role of increased signaling by these gut hormones in high-fat diet-induced obese rodents. Chronic brain infusion of a supramaximal dose of the selective GLP-1 receptor antagonist exendin-9-39 into the lateral cerebral ventricle significantly increased food intake and body weight in both RYGB and sham-operated rats, suggesting that, while contributing to the physiological control of food intake and body weight, central GLP-1 receptor signaling tone is not the critical mechanism uniquely responsible for the body weight-lowering effects of RYGB. Central infusion of the selective Y2R-antagonist BIIE0246 had no effect in either group, suggesting that it is not critical for the effects of RYGB on body weight under the conditions tested. In a recently established mouse model of RYGB that closely mimics surgery and weight loss dynamics in humans, obese GLP-1R-deficient mice lost the same amount of body weight and fat mass and maintained similarly lower body weight compared with wild-type mice. Together, the results surprisingly provide no support for important individual roles of either gut hormone in the specific mechanisms by which RYGB rats settle at a lower body weight. It is likely that the beneficial effects of bariatric surgeries are expressed through complex mechanisms that require combination approaches for their identification.
authors.affiliation: Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana;
authors.forename: Jianping
authors.initials: J
authors.lastname: Ye
authors.forename: Zheng
authors.initials: Z
authors.lastname: Hao
authors.forename: Michael B
authors.initials: MB
authors.lastname: Mumphrey
authors.forename: R Leigh
authors.initials: RL
authors.lastname: Townsend
authors.forename: Laurel M
authors.initials: LM
authors.lastname: Patterson
authors.forename: Nicholas
authors.initials: N
authors.lastname: Stylopoulos
authors.forename: Heike
authors.initials: H
authors.lastname: Münzberg
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Morrison
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
authors.forename: Hans-Rudolf
authors.initials: HR
authors.lastname: Berthoud
mesh_terms: D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology; D001823:Body Composition; D001835:Body Weight / Q000187:drug effects; D004041:Dietary Fats; D004435:Eating; D004734:Energy Metabolism; D015390:Gastric Bypass; D000067757:Glucagon-Like Peptide-1 Receptor; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity; D009765:Obesity / Q000378:metabolism / Q000601:surgery; D010101:Oxygen Consumption; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015431:Weight Loss / Q000502:physiology*
chemical_list: D001552:Benzazepines; D004041:Dietary Fats; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D010446:Peptide Fragments; D018027:Receptors, Glucagon; C083773:exendin (9-39); D001120:Arginine; C403256:BIIE 0246
keywords: GLP-1R knockout; Roux-en-Y gastric bypass; brain; exendin-(9–39), BIIE0246; food intake; gut hormones; high-fat diet