Abstract:
:Members of the muscarinic acetylcholine receptor family (M1-M5) have central roles in the regulation of many fundamental physiological functions. 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 ligands. 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 intake, 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.
journal_name
Naturejournal_title
Natureauthors
Yamada M,Miyakawa T,Duttaroy A,Yamanaka A,Moriguchi T,Makita R,Ogawa M,Chou CJ,Xia B,Crawley JN,Felder CC,Deng CX,Wess Jdoi
10.1038/35065604keywords:
subject
Has Abstractpub_date
2001-03-08 00:00:00pages
207-12issue
6825eissn
0028-0836issn
1476-4687pii
35065604journal_volume
410pub_type
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