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-(2,4dichlorophenyl)-4-methyl-1H-p yrazole-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 I 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. (c) 2008 Elsevier B.V All rights reserved.