Aims: Energy homeostasis is regulated by a complex interaction of molecules and pathways, and new antiobesity treatments are likely to require multiple pharmacological targeting of anorexigenic or orexigenic pathways to achieve effective loss of excess body weight and adiposity. Cannabinoids, acting via the cannabinoid‐1 (CB1) receptor, and neuropeptide Y (NPY) are important modulators of feeding behaviour, energy metabolism and body composition. We investigated the interaction of CB1 and NPY in the regulation of energy homeostasis, hypothesizing that dual blockade of CB1 and NPY signalling will induce greater weight and/or fat loss than that induced by single blockade of either system alone.

Methods: We studied the effects of the CB1 antagonist Rimonabant on food intake, body weight, body composition, energy metabolism and bone physiology in wild‐type (WT) and NPY knockout (NPY^−/−) mice. Rimonabant was administered orally at 10 mg/kg body weight twice per day for 3 weeks. Oral Rimonabant was delivered voluntarily to mice via a novel method enabling studies to be carried out in the absence of gavage‐induced stress.

Results: Mice with dual blockade of CB1 and NPY signalling (Rimonabant‐treated NPY^−/− mice) exhibited greater reductions in body weight and adiposity than mice with single blockade of either system alone (Rimonabant‐treated WT or vehicle‐treated NPY^−/− mice). These changes occurred without loss of lean tissue mass or bone mass. Furthermore, Rimonabant‐treated NPY^−/− mice showed a lower respiratory exchange ratio than that seen in Rimonabant‐treated WT or vehicle‐treated NPY^−/− mice, suggesting that this additive effect of dual blockade of CB1 and NPY involves promotion of lipid oxidation. On the other hand, energy expenditure and physical activity were comparable amongst all treatment groups. Interestingly, Rimonabant similarly and transiently reduced spontaneous and fasting‐induced food intake in WT and NPY^−/− mice in the first hour after administration only, suggesting independent regulation of feeding by CB1 and NPY signalling. In contrast, Rimonabant increased serum corticosterone levels in WT mice, but this effect was not seen in NPY^−/− mice, indicating that NPY signalling may be required for effects of CB1 on the hypothalamo‐pituitary‐adrenal axis.

Conclusions: Dual blockade of CB1 and NPY signalling leads to additive reductions in body weight and adiposity without concomitant loss of lean body mass or bone mass. An additive increase in lipid oxidation in dual CB1 and NPY blockade may contribute to the effect on adiposity. These findings open new avenues for more effective treatment of obesity via dual pharmacological manipulations of the CB1 and NPY systems.