Identification of receptors for neuromedin U and its role in feeding

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Abstract
Neuromedin U (NMU) is a neuropeptide with potent activity on smooth muscle which was isolated first from porcine spinal cord and later from other species1,2,3,4,5,6,7,8. It is widely distributed in the gut and central nervous system9,10. Peripheral activities of NMU include stimulation of smooth muscle1, increase of blood pressure1, alteration of ion transport in the gut11, control of local blood flow12,13 and regulation of adrenocortical function14. An NMU receptor has not been molecularly identified. Here we show that the previously described orphan G-protein-coupled receptor FM-3 (ref. 15) and a newly discovered one (FM-4) are cognate receptors for NMU. FM-3, designated NMU1R, is abundantly expressed in peripheral tissues whereas FM-4, designated NMU2R, is expressed in specific regions of the brain. NMU is expressed in the ventromedial hypothalamus in the rat brain, and its level is significantly reduced following fasting. Intracerebroventricular administration of NMU markedly suppresses food intake in rats. These findings provide a molecular basis for the biochemical activities of NMU and may indicate that NMU is involved in the central control of feeding.