Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean

Masahisa Yamada, Tsuyoshi Miyakawa, Alokesh Duttaroy, Akihiro Yamanaka, Toru Moriguchi, Ryosuke Makita, Masaharu Ogawa, Chieh J. Chou, Bing Xia, Jacqueline N. Crawley, Christian C. Felder, Chu-Xia Deng and Jürgen Wess ()
Additional contact information
Masahisa Yamada: Laboratory of Bioorganic Chemistry
Tsuyoshi Miyakawa: Experimental Therapeutics Branch, National Institute of Mental Health
Alokesh Duttaroy: Laboratory of Bioorganic Chemistry
Akihiro Yamanaka: Institute of Basic Medical Sciences, University of Tsukuba
Toru Moriguchi: Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism
Ryosuke Makita: Laboratory for Cell Culture Development, RIKEN Brain Science Institute
Masaharu Ogawa: Laboratory for Cell Culture Development, RIKEN Brain Science Institute
Chieh J. Chou: Diabetes Branch
Bing Xia: Laboratory of Bioorganic Chemistry
Jacqueline N. Crawley: Experimental Therapeutics Branch, National Institute of Mental Health
Christian C. Felder: Lilly Research Laboratories, Eli Lilly and Company
Chu-Xia Deng: National Institute of Diabetes and Digestive and Kidney Diseases
Jürgen Wess: Laboratory of Bioorganic Chemistry

Nature, 2001, vol. 410, issue 6825, 207-212

Abstract: 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.

Date: 2001
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DOI: 10.1038/35065604

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