The hypothesis that the melanocortin MC4 receptor mediates the homeostatic effects of leptin was tested. Leptin (0.3 nmol, i.c.v.) lowered food intake at 4 and 24 h and body weight at 24 h. This effect was inhibited by pretreatment with an analogue of melanocyte stimulating hormone (MSH), the selective melanocortin MC4 receptor antagonist HS014 (cyclic [AcCys11,D-Nal14,Cys18,Asp-NH2(22)]-beta-MSH11-2 2, 0.3 nmol, i.c.v.). HS014 alone at this dose did not modify food intake or body weight. At a higher dose (1.0 nmol, i.c.v.) HS014 stimulated food intake and this orexigenic effect of HS014 was attenuated by leptin pretreatment (0.3 nmol, i.c.v.). These results confirm earlier findings that leptin inhibits food intake and lowers body weight via the melanocortin system and suggest that leptin affects signalling at the melanocortin MC4 receptor.