Author
Listed:
- Masahisa Yamada
(Laboratory of Bioorganic Chemistry
Laboratory for Cell Culture Development, RIKEN Brain Science Institute)
- Tsuyoshi Miyakawa
(Experimental Therapeutics Branch, National Institute of Mental Health
Vanderbilt University Medical Center)
- 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)
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.
Suggested Citation
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 & , 2001.
"Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean,"
Nature, Nature, vol. 410(6825), pages 207-212, March.
Handle:
RePEc:nat:nature:v:410:y:2001:i:6825:d:10.1038_35065604
DOI: 10.1038/35065604
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