Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean

Members of the muscarinic acetylcholine receptor family (M1-M5) have centra l roles in the regulation of many fundamental physiological functions(1,2). Identifying the specific receptor subtype( s) that mediate the diverse mus carinic actions of acetylcholine is of considerable therapeutic interest, b ut has proved difficult primarily because of a lack of subtype-selective li gands(3). Here we show that mice deficient in the M3 muscarinic receptor (M 3R(-/-) mice) display a significant decrease in food intake, reduced body w eight and peripheral fat deposits, and very low levels of serum leptin and insulin. Paradoxically, hypothalamic messenger RNA levels of melanin-concen trating hormone (MCH), which are normally upregulated in fasted animals lea ding to an increase in food intake(4,5), are significantly reduced in M3R(- /-) mice. Intra-cerebroventricular injection studies show that an agouti-re lated peptide analogue lacked orexigenic (appetite-stimulating) activity in M3R(-/-) mice. However, M3R(-/-) mice remained responsive to the orexigeni c 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 d ownstream of the hypothalamic leptin/melanocortin system and upstream of th e MCH system.