The central melanocortin system is involved in the regulation of food intake and body weight. In this study, we investigated the effect of a 4-week intracerebroventricular infusion of the melanocortin receptor agonist MT-II and the selective melanocortin-4 receptor antagonist HS024 on food intake and body weight homeostasis. The MT-II-treated rats ate less and lost considerably more weight than the control rats during the first week of treatment. During the second and third week, they gained weight and, by the end of the treatment period, the weight gain was similar to that of the control rats. The HS024 treatment caused hyperphagia and development of obesity during the entire period. Extensive accumulations of fat and a sixfold increase in leptin levels were observed in the HS024-treated rats, as compared with controls, after the 4-week period. Food conversion ratio, defined as body weight increase relative to weight of ingested food, was clearly increased in the HS024-treated rats, while it was lowered in the MT-II-treated rats compared with controls. The effect on food conversion ratio was transient, being greatest for both experimental groups during the first week and it was then attenuated to reach the level of controls at the end of the study. The results suggest that long-term injection of exogenous melanocortin receptor active substances may have an important transient effect on food conversion.