Antiobesity effects of chronic cannabinoid CB1 receptor antagonist treatment in diet-induced obese mice.
We determined the effect of a cannabinoid CB1 receptor antagonist (AM-251; N-(Piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide) on food intake, body weight and adipose tissue mass in Western diet-induced obese (DIO) mice using a chronic, interrupted, oral dosing paradigm. The dosing paradigm was 2 weeks on treatment (treatment 1), 2 weeks off-treatment, followed by 2 weeks on treatment (treatment 2). During treatment 1 and treatment 2, food intake and body weight were reduced after a single dose. At 30 mg/kg/day, anorectic efficacy was maintained through 12 days (treatment 1) and 7 days (treatment 2). Body weight of AM-251-treated mice remained less than vehicle-treated mice throughout treatment 1 and treatment 2. Administration of AM-251 reduced inguinal subcutaneous, retroperitoneal and mesenteric adipose tissue mass. Antiobesity effects of AM-251 were lost during the off-treatment period, and hyperphagia was observed in treated animals. With re-initiation of AM-251 treatment, mice again responded to the effects of the compound. These results support the hypothesis that chronic treatment of obese individuals with cannabinoid CB1 receptor antagonists is a viable pharmacologic approach to sustained weight loss.
Hildebrandt
Audrey L
AL
Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Eastern Point Road, MS 8220-3119, Groton, CT 06340, USA.
Kelly-Sullivan
Dawn M
DM
Black
Shawn C
SC
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D004041:Dietary Fats / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors*; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin; D020738:Leptin; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D014280:Triglycerides; C103505:AM 251; D002784:Cholesterol