Melanin-concentrating hormone is the cognate ligand for the orphan G-protein-coupled receptor SLC-1

The underlying causes of obesity are poorly understood but probably involve complex interactions between many neurotransmitter and neuropeptide system s involved in the regulation of food intake and energy balance. Three piece s of evidence indicate that the neuropeptide melanin-concentrating hormone (MCH) is an important component of this system. First, MCH stimulates feedi ng when injected directly into rat brains(1,2); second, the messenger RNA f or the MCH precursor is upregulated in the hypothalamus of genetically obes e mice and in fasted animals'; and third, mice lacking MCH eat less and are lean(3). MCH antagonists might, therefore, provide a treatment for obesity . However, the development of such molecules has been hampered because the identity of the MCH receptor has been unknown until now. Here we show that the 353-amino-acid human orphan G-protein-coupled receptor SLC-1 (ref, 4) e xpressed in HEK293 cells binds MCH with sub-nanomolar affinity, and is stim ulated by MCH to mobilize intracellular Ca2+ and reduce forskolin-elevated cyclic AMP levels. We also show that SLC-1 messenger RNA and protein is exp ressed in the ventromedial and dorsomedial nuclei of the hypothalamus, cons istent with a role for SLC-1 in mediating the effects of MCH on feeding.