Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean

Nature volume 410, pages207–212(2001)Cite this article

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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Figure 1: Targeted disruption of the mouse M3 muscarinic receptor gene.
Figure 2: Body weight, food intake, mass of peripheral fat pads, metabolic rate and salivation response of wild-type and M3R-/- mice.
Figure 3: Glucose and insulin tolerance tests for wild-type and M3R-/- mice.
Figure 4: Role of M3 muscarinic receptors in neuropeptide-mediated feeding behaviour.

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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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Author notes

  1. Tsuyoshi Miyakawa

    Present address: Department of Pharmacology & Center for Molecular Neuroscience, Vanderbilt University Medical Center, Nashville, Tennessee, 37232-6600, USA

Affiliations

  1. Laboratory of Bioorganic Chemistry

    Masahisa Yamada, Alokesh Duttaroy, Bing Xia & Jürgen Wess

  2. Diabetes Branch

    Chieh J. Chou

  3. Laboratory of Biochemistry and Metabolism, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, 20892, Maryland, USA

    Chu-Xia Deng

  4. Laboratory for Cell Culture Development, RIKEN Brain Science Institute, Wako-shi, 351-0198, Saitama, Japan

    Masahisa Yamada, Ryosuke Makita & Masaharu Ogawa

  5. Section on Behavioral Pharmacology, Experimental Therapeutics Branch, National Institute of Mental Health, Bethesda, 20892, Maryland, USA

    Tsuyoshi Miyakawa & Jacqueline N. Crawley

  6. Department of Pharmacology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, 305-8575, Ibaraki, Japan

    Akihiro Yamanaka

  7. Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Rockville, 20852, Maryland, USA

    Toru Moriguchi

  8. Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, 46285, Indiana, USA

    Christian C. Felder

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Correspondence to Jürgen Wess.

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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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