Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean.

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

Nature

journal_title

Nature

authors

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 J

doi

10.1038/35065604

keywords:

subject

Has Abstract

pub_date

2001-03-08 00:00:00

pages

207-12

issue

6825

eissn

0028-0836

issn

1476-4687

pii

35065604

journal_volume

410

pub_type

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