GLP-1 receptor signaling is not required for reduced body weight after RYGB in rodents

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology Vol. 306; no. 5; p. R352
• Main Authors: Ye, Jianping, Hao, Zheng, Mumphrey, Michael B, Townsend, R Leigh, Patterson, Laurel M, Stylopoulos, Nicholas, Münzberg, Heike, Morrison, Christopher D, Drucker, Daniel J, Berthoud, Hans-Rudolf
• Format: Journal Article
• Language: English
• Published: United States 01-03-2014
• Subjects: Animals; Arginine - administration & dosage; Arginine - analogs & derivatives; Arginine - pharmacology; Benzazepines - administration & dosage; Benzazepines - pharmacology; Body Composition; Body Weight - drug effects; Dietary Fats; Eating; Energy Metabolism; Gastric Bypass; Glucagon-Like Peptide-1 Receptor; Male; Mice; Mice, Knockout; Motor Activity; Obesity - metabolism; Obesity - surgery; Oxygen Consumption; Peptide Fragments - administration & dosage; Peptide Fragments - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Glucagon - antagonists & inhibitors; Receptors, Glucagon - genetics; Receptors, Glucagon - metabolism; Weight Loss - physiology; exendin-(9–39), BIIE0246; Roux-en-Y gastric bypass; GLP-1R knockout; gut hormones; high-fat diet; brain; food intake
• ISSN: 1522-1490
• DOI: 10.1152/ajpregu.00491.2013

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.