Neuromedin U (NMU) is known to have potent actions on appetite and energy expenditure. Deletion of the NMU gene in mice leads to an obese phenotype, characterized by hyperphagia and decreased energy expenditure. Conversely, transgenic mice that over express pro-NMU exhibit reduced body weight and fat storage. Here we show that central administration of NMU, or the related peptide neuromedin S (NMS) dose-dependently decreases food intake, increases metabolic rate, and leads to significant weight loss in mice. The effects of NMU and NMS on both feeding and metabolism are almost completely lost in mice lacking the putative CNS receptor for NMU and NMS, NMUr2. However, NMUr2 knockout mice do not exhibit overt differences in body weight or energy expenditure when compared with wild type mice, suggesting that the dramatic phenotype of the NMU gene knockout mouse is not due simply to the loss of NMU-NMUr2 signalling. Putative proteolytic cleavage sites indicate that an additional peptide is produced from the NMU precursor protein, which is extremely well conserved between human, mouse and rat. Here we demonstrate that this peptide, proNMU_104-136 has a pronounced effect on energy balance in mice. Specifically, central administration of proNMU_104-136 causes a significant but transient (~4hr) increase in feeding, yet both food intake and body weight are decreased over the following 24hr. proNMU_104-136 administration also significantly increased metabolic rate. These results suggest that proNMU_104-136 is a novel modulator of energy balance, and may contribute to the phenotype exhibited by NMU knockout mice.