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.