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Mice lacking melanin-concentrating hormone are hypophagic and lean

Abstract

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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Figure 1: Targeted disruption of the MCH gene in mice.
Figure 2: Body weight, fat composition and food intake in MCH−/− and control mice fed on a chow diet.
Figure 3: Leptin levels and feeding response in MCH−/− mice.
Figure 4: Response of six MCH+/+ (open circles) and six MCH−/− mice (shaded circles) to recombinant mouse leptin, administered at a dose of 1 µg per g body weight twice daily (09:00 and 18:00), vs saline control (n = 3; triangles).
Figure 5: Expression of neuropeptide mRNAs in hypothalami of 24-week-old wild-type (n = 6; white bars) and MCH−/− (n = 6; shaded bars) mice.

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Acknowledgements

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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  1. Eleftheria Maratos-Flier: Correspondence and requests for materials should be addressed to E.M.-F

    • Eleftheria Maratos-Flier
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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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