Antidiabetic effects of sub-chronic administration of the cannabinoid receptor (CB1) antagonist, AM251, in obese diabetic (ob/ob) mice

Eur J Pharmacol. 2008 Feb 26;581(1-2):226-33. doi: 10.1016/j.ejphar.2007.12.003. Epub 2007 Dec 14.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / analysis
  • Body Weight / drug effects
  • Eating / drug effects
  • Female
  • Hypoglycemic Agents / pharmacology*
  • Insulin / blood
  • Insulin Resistance
  • Male
  • Mice
  • Mice, Obese
  • Motor Activity / drug effects
  • Piperidines / pharmacology*
  • Pyrazoles / pharmacology*
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors*

Substances

  • Blood Glucose
  • Hypoglycemic Agents
  • Insulin
  • Piperidines
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • AM 251