BACKGROUND AND PURPOSE Peripheral blockade of cannabinoid CB1 receptors has been proposed as a safe and effective therapy against obesity, putatively devoid of the adverse psychiatric side effects of centrally acting CB1 receptor antagonists. In this study we analysed the effects of LH‐21, a peripherally acting neutral cannabinoid receptor antagonist with poor brain penetration, in an animal model of diet‐induced obesity.EXPERIMENTAL APPROACH To induce obesity, male Wistar rats were fed a high‐fat diet (HFD; 60 kcal% fat) whereas controls received a standard diet (SD; 10 kcal% fat). Following 10 weeks of feeding, animals received a daily i.p. injection of vehicle or 3 mg·kg−1 LH‐21 for 10 days. Plasma and liver samples were used for biochemical analyses whereas visceral fat‐pad samples were analysed for lipid metabolism gene expression using real‐time RT‐PCR. In addition, the potential of LH‐21 to interact with hepatic cytochrome P450 isoforms and cardiac human Ether‐à‐go‐go Related Gene (hERG) channels was evaluated.KEY RESULTS LH‐21 reduced feeding and body weight gain in HFD‐fed animals compared with the control group fed SD. In adipose tissue, this effect was associated with decreased gene expression of: (i) leptin; (ii) lipogenic enzymes, including SCD‐1; (iii) CB1 receptors; and (iv) both PPARα and PPARγ. Although there were no significant differences in plasma parameters between HFD‐ and SD‐fed rats, LH‐21 did not seem to induce hepatic, cardiac or renal toxicity.CONCLUSIONS AND IMPLICATIONS These results support the hypothesis that treatment with the peripherally neutral acting CB1 receptor antagonist, LH‐21, may promote weight loss through modulation of visceral adipose tissue.