title: Antidiabetic effects of sub-chronic administration of the cannabinoid receptor (CB1) antagonist, AM251, in obese diabetic (ob/ob) mice.
abstract: Recent research suggests that cannabinoid CB1 receptor antagonism reduces appetite and body weight gain. The present study was designed to assess the sub-chronic effects of the selective cannabinoid CB1 receptor antagonist, AM251 (N-(Piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide), in young ob/ob mice. Pair-fed animals were used as additional controls. Daily injection of AM251 (6 mg/kg body weight) for 18 days significantly (P<0.05) decreased daily and 18-day cumulative food intake. The corresponding body weight change did not achieve significance and values were not different from pair-fed mice. Non-fasting plasma glucose was decreased (P<0.05) from day 10 onwards by AM251 treatment. The glycaemic response to intraperitoneal glucose was correspondingly improved (P<0.05) in AM251 treated mice. In keeping with this, insulin sensitivity was enhanced (P<0.05) compared to controls. Furthermore, adipose mRNA levels of acetyl-CoA carboxylase 1 were significantly (P<0.05) reduced by 18 days AM251 treatment. There were no differences in either non-fasting or glucose-stimulated insulin release. Pair-feeding had broadly similar metabolic effects to AM251 treatment apart from increased (P<0.01) locomotor activity which was only observed in AM251 treated ob/ob mice. These data indicate that sub-chronic antagonism of the cannabinoid CB1 receptor by daily treatment with AM251 counters aspects of the hyperphagia-related impairment of ob/ob mouse metabolism. Such effects seem predominantly mediated by restriction of energy intake.
authors.affiliation: School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, United Kingdom. n.irwin@ulster.ac.uk
authors.forename: Nigel
authors.initials: N
authors.lastname: Irwin
authors.forename: Kerry
authors.initials: K
authors.lastname: Hunter
authors.forename: Norma
authors.initials: N
authors.lastname: Frizzell
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005260:Female; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009043:Motor Activity / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C103505:AM 251