Abstract
Members of the muscarinic acetylcholine receptor family (M1–M5) have central roles in the regulation of many fundamental physiological functions1,2. Identifying the specific receptor subtype(s) that mediate the diverse muscarinic actions of acetylcholine is of considerable therapeutic interest, but has proved difficult primarily because of a lack of subtype-selective ligands3. Here we show that mice deficient in the M3 muscarinic receptor (M3R-/- mice) display a significant decrease in food intake, reduced body weight and peripheral fat deposits, and very low levels of serum leptin and insulin. Paradoxically, hypothalamic messenger RNA levels of melanin-concentrating hormone (MCH), which are normally upregulated in fasted animals leading to an increase in food intake4,5, are significantly reduced in M3R-/- mice. Intra-cerebroventricular injection studies show that an agouti-related peptide analogue lacked orexigenic (appetite-stimulating) activity in M3R-/- mice. However, M3R-/- mice remained responsive to the orexigenic effects of MCH. Our data indicate that there may be a cholinergic pathway that involves M3-receptor-mediated facilitation of food intake at a site downstream of the hypothalamic leptin/melanocortin system and upstream of the MCH system.
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Acknowledgements
This research was supported by the JSPS Research Fellowship Program (M.Y.) and through a CRADA between the NIDDK and the Eli Lilly Research Laboratories (B.X.). We thank M. L. Reitman, H. Kodama, H. Kanki and T. Sakurai for advice and discussions; J. Gan, N. Tsujino and C. Li for technical assistance; R. A. Kesterson for critical reading of the manuscript; and A. M. Spiegel and I. W. Levin for support of this work.
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Yamada, M., Miyakawa, T., Duttaroy, A. et al. Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean. Nature 410, 207–212 (2001). https://doi.org/10.1038/35065604
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DOI: https://doi.org/10.1038/35065604
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