Appetite-modifying actions of pro-neuromedin U-derived peptides.
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 overexpress proNMU 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 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 signaling. 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 ( approximately 4 h) increase in feeding, yet both food intake and body weight are decreased over the following 24 h. 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.
Bechtold
David A
DA
Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
Ivanov
Tina R
TR
Luckman
Simon M
SM
D000595:Amino Acid Sequence; D000818:Animals; D000855:Anorexia / Q000139:chemically induced; D001069:Appetite Regulation / Q000187:drug effects*; D004734:Energy Metabolism / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009479:Neuropeptides / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D011498:Protein Precursors / Q000737:chemistry / Q000494:pharmacology*; D017981:Receptors, Neurotransmitter / Q000235:genetics; D017386:Sequence Homology, Amino Acid
D009479:Neuropeptides; D010446:Peptide Fragments; D011498:Protein Precursors; D017981:Receptors, Neurotransmitter; C497950:neuromedin S; C082444:neuromedin U receptor; C056900:neuromedin U