Feeding is influenced by hypothalamic neuropeptides that promote (orexigenic peptides) or inhibit feeding1. Of these, neuropeptide Y (NPY) in the arcuate nucleus2 and melanin-concentrating hormone (MCH)3 and orexins/hypocretins4,5 in the lateral hypothalamus have received attention because their expression is increased during fasting and because they promote feeding when administered centrally. Surprisingly, absence of the orexigenic neuropeptide NPY fails to alter feeding or body weight in normal mice6. As deficiency of a single component of the pathway that limits food intake (such as leptin or receptors for melanocortin-4)7,8 causes obesity, it has been suggested that orexigenic signals are more redundant than those limiting food intake7,8. To define further the physiological role of MCH and to test the redundancy of orexigenic signals, we generated mice carrying a targeted deletion of the MCH gene. MCH-deficient mice have reduced body weight and leanness due to hypophagia (reduced feeding) and an inappropriately increased metabolic rate, despite their reduced amounts of both leptin and arcuate nucleus pro-opiomelanocortin messenger RNA. Our results show that MCH is a critical regulator of feeding and energy balance which acts downstream of leptin and the melanocortin system, and that deletion of a gene encoding a single orexigenic peptide can result in leanness.
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We thank J. Mastaitis, C. Behn and C. Lee for technical assistance, J. Elmquist for help in analysing and interpreting brain anatomy, and D. S. Ludwig for the P1 clone used in making the construct for the knockout mice. This work was supported in part by grants from NIH to J.S.F. and E.M.-F., from the American Diabetes Association to E.M.-F., and from Eli Lilly to J.S.F. and E.M.-F., and by the Transgenic Core of the Boston Obesity Nutrition Research Center. M.S. was supported by the Banyu Fellowship in Lipid Metabolism and Atherosclerosis which is sponsored by Banyu Pharmaceutical Co Ltd and the Merck Foundation.
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Shimada, M., Tritos, N., Lowell, B. et al. Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature 396, 670–674 (1998). https://doi.org/10.1038/25341
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