Response of melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides

Mutations reducing the functional activity of leptin(1,2), the leptin recep tor(3,4), alpha-melanocyte stimulating hormone(5) (alpha-MSH) and the melan ocortin-4 receptor(6) (Mc4r) all lead to obesity in mammals. Moreover, muta nt mice that ectopically express either agouti(7) (Aula mice) or agouti-rel ated protein(8) (Agrp), antagonists of melanocortin signalling(8,9), become obese. These data suggest that alpha-MSH signalling transduced by Mc4r ton ically inhibits feeding; however, it is not known to what extent this pathw ay mediates leptin signalling. We show here that Mc4r-deficient (Mc4r(-/-)) mice do not respond to the anorectic actions of MTII, an MSH-like agonist, suggesting that alpha-MSH inhibits feeding primarily by activating Mc4r. O bese Mc4(-/-) mice do not respond significantly to the inhibitory effects o f leptin on feeding, whereas non-obese Mc4r(-/-) mice do. These data demons trate that melanocortin signalling transduced by Mc4r is not an exclusive t arget of leptin action and that factors resulting from obesity contribute t o leptin resistance. Leptin resistance of obese Mc4r(-/-) mice does not pre vent their response to the anorectic actions of ciliary neurotrophic factor (CNTF), corticotropin releasing factor (CRF), or urocortin; or the orexige nic actions of neuropeptide Y (NPY) or peptide YY (PYY), indicating that th ese neuromodulators act independently or downstream of Mdr signalling.