The effect of leptin on the expression of melanin-concentrating hormone (MCH) was investigated in lean and genetically obese Lepob/Lepob mice. Murine leptin was subcutaneously infused using osmotic minipumps. The treatment period extended to 7 days and the daily dose of leptin delivered was 100 microgram/kg of body weight. In situ hybridization was used to assess the effects of leptin infusion on the expression of MCH mRNA. MCH levels in the brain (hypothalamus/thalamus and the remaining part), spleen and testis were measured by radioimmunoassay coupled to HPLC of selected tissue extracts. Leptin significantly reduced final body weight, weight of brown adipose tissue, daily food intake in obese mice but not in lean animals. In obese mice, leptin led to a rapid reduction in food intake which reached statistical significance after only 24 h and which led to a significant reduction in the body weight after 3 days of treatment. Leptin restored the normal circulating levels of glucose and insulin in obese mice. The present results mainly provide evidence for a stimulating effect of leptin infusion on the MCH neuronal system. The hypothalamic/thalamic levels of MCH mRNA and peptide were higher in mice treated with leptin than in mice infused with phosphate-buffered saline. The stimulation of MCH neurons appeared particularly intense in obese mice, in which the effects of leptin infusion led to the reduction in MCH content of neuron fibers and terminals. Leptin did not affect spleen and testis MCH contents. In the light of the acknowledged orexigenic effects of MCH, the results of this study questioned the direct role of MCH in the action of leptin on energy balance. The increase in MCH expression following leptin could occur as a mechanism to compensate the decrease in energy deposition led to by leptin. It may also indicate that MCH mediates the metabolic actions of leptin indirectly or else that leptin influences actions of MCH other than those related to the regulation of energy balance.