BACKGROUND & AIMS:: Specific neuronal circuits modulate autonomic outflow to liver and white adipose tissue. Melanin-concentrating hormone (MCH) deficient mice are hypophagic, lean and do not develop hepatosteatosis when fed on high fat diet. Herein, we sought to investigate the role of melanin-concentrating hormone (MCH), an orexigenic neuropeptide specifically expressed in the lateral hypothalamic area (LHA), on hepatic and adipocyte metabolism. METHODS:: Chronic central administration of MCH and adenoviral vectors increasing MCH signalling were performed in rats and mice. Vagal dennervation was done to assess its effect on liver metabolism. The peripheral effects on lipid metabolism were assessed by real-time PCR and western blot. RESULTS:: We demonstrate that the activation of MCH receptors (MCH-R) promotes nonalcoholic fatty liver disease (NAFLD) through the parasympathetic nervous system (PSNS), whereas it increases fat deposition in WAT via the suppression of sympathetic traffic. These metabolic actions are independent of parallel changes in food intake and energy expenditure. In the liver, MCH triggers lipid accumulation and lipid uptake, being c-Jun N-terminal kinase (JNK1) an essential player, while in adipocytes MCH induces metabolic pathways that promote lipid storage and decreases lipid mobilization. Genetic activation of MCH-R or infusion of MCH specifically in the LHA modulated hepatic lipid metabolism, whereas the specific activation of this receptor in the arcuate nucleus (ARC) affected adipocyte metabolism. CONCLUSIONS:: Our findings reveal that central MCH directly controls hepatic and adipocyte metabolism through different pathways.