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The Antiobesity Effects of Centrally Administered Neuromedin U and Neuromedin S Are Mediated Predominantly by the Neuromedin U Receptor 2 (NMUR2)

Merck Research Laboratories, Department of Metabolic Disorders, Rahway, New Jersey 07065

Address all correspondence and requests for reprints to: Donald J. Marsh, Merck Research Laboratories, Department of Metabolic Disorders, 126 East Lincoln Avenue, RY80L-126, Rahway, New Jersey 07065. E-mail: donald_marsh{at}merck.com.

Neuromedin U (NMU) and neuromedin S (NMS) are structurally related neuropeptides that have been reported to modulate energy homeostasis. Pharmacological data have shown that NMU and NMS inhibit food intake when administered centrally and that NMU increases energy expenditure. Additionally, NMU-deficient mice develop obesity, whereas transgenic mice overexpressing NMU are lean and hypophagic. Two high-affinity NMU/NMS receptors, NMUR1 and NMUR2, have been identified. NMUR1 is predominantly expressed in the periphery, whereas NMUR2 is predominantly expressed in the brain, suggesting that the effects of centrally administered NMU and NMS are mediated by NMUR2. To evaluate the role of NMUR2 in the regulation of energy homeostasis, we characterized NMUR2-deficient (Nmur2^–/–) mice. Nmur2^–/– mice exhibited a modest resistance to diet-induced obesity that was at least in part due to reduced food intake. Acute central administration of NMU and NMS reduced food intake in wild-type but not in Nmur2^–/– mice. The effects on activity and core temperature induced by centrally administered NMU were also absent in Nmur2^–/– mice. Moreover, chronic central administration of NMU and NMS evoked significant reductions in body weight and sustained reductions in food intake in mice. In contrast, Nmur2^–/– mice were largely resistant to these effects. Collectively, these data demonstrate that the anorectic and weight-reducing actions of centrally administered NMU and NMS are mediated predominantly by NMUR2, suggesting that NMUR2-selective agonists may be useful for the treatment of obesity.

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