title: Cannabinoid receptor 1 antagonist treatment induces glucagon release and shows an additive therapeutic effect with GLP-1 agonist in diet-induced obese mice.
abstract: Cannabinoid 1 (CB1) receptor antagonists reduce body weight and improve insulin sensitivity. Preclinical data indicates that an acute dose of CB1 antagonist rimonabant causes an increase in blood glucose. A stable analog of glucagon-like peptide 1 (GLP-1), exendin-4 improves glucose-stimulated insulin secretion in pancreas, and reduces appetite through activation of GLP-1 receptors in the central nervous system and liver. We hypothesized that the insulin secretagogue effect of GLP-1 agonist exendin-4 may synergize with the insulin-sensitizing action of rimonabant. Intraperitoneal as well as intracerebroventricular administration of rimonabant increased serum glucose upon glucose challenge in overnight fasted, diet-induced obese C57 mice, with concomitant rise in serum glucagon levels. Exendin-4 reversed the acute hyperglycemia induced by rimonabant. The combination of exendin-4 and rimonabant showed an additive effect in the food intake, and sustained body weight reduction upon repeated dosing. The acute efficacy of both the compounds was additive for inducing nausea-like symptoms in conditioned aversion test in mice, whereas exendin-4 treatment antagonized the effect of rimonabant on forced swim test upon chronic dosing. Thus, the addition of exendin-4 to rimonabant produces greater reduction in food intake owing to increased aversion, but reduces the other central nervous system side effects of rimonabant. The hyperglucagonemia induced by rimonabant is partially responsible for enhancing the antiobesity effect of exendin-4.
authors.affiliation: a Department of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Sarkhej-Bavla N.H. No. 8A, Moraiya, Ahmedabad 382210, India.
authors.forename: Kartikkumar Navinchandra
authors.initials: KN
authors.lastname: Patel
authors.forename: Amit Arvind
authors.initials: AA
authors.lastname: Joharapurkar
authors.forename: Vishal
authors.initials: V
authors.lastname: Patel
authors.forename: Samadhan Govind
authors.initials: SG
authors.lastname: Kshirsagar
authors.forename: Rajesh
authors.initials: R
authors.lastname: Bahekar
authors.forename: Brijesh Kumar
authors.initials: BK
authors.lastname: Srivastava
authors.forename: Mukul R
authors.initials: MR
authors.lastname: Jain
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D059305:Diet, High-Fat; D004357:Drug Synergism; D004435:Eating / Q000187:drug effects; D000077270:Exenatide; D005934:Glucagon / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000819:agonists* / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077285:Rimonabant; D014688:Venoms / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D019440:Anti-Obesity Agents; D001786:Blood Glucose; D010455:Peptides; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000077270:Exenatide; D000077285:Rimonabant
keywords: exendin-4; exendine-4; hyperglycemia; hyperglycémie; insulin; insuline; rimonabant