ROLE OF MELANOCORTINERGIC NEURONS IN FEEDING AND THE AGOUTI OBESITY SYNDROME

DOMINANT alleles at the agouti locus (A) cause an obesity syndrome in the mouse, as a consequence of ectopic expression of the agouti peptid e(1-6). This peptide, normally only found in the skin, is a high-affin ity antagonist of the melanocyte-stimulating hormone receptor (MC1-R)( 7), thus explaining the inhibitory effect of agouti on eumelanin pigme nt synthesis, The agouti peptide is also an antagonist of the hypothal amic melanocortin-4 receptor (MC4-R)(7-9). To test the hypothesis that agouti causes obesity by antagonism of hypothalamic melanocortin rece ptors(7), we identified cyclic melanocortin analogues(10) that are pot ent agonists or antagonists of the neural MC3 (refs 11, 12) and MC4 re ceptors. Intracerebroventricular administration of the agonist, MTII, inhibited feeding in four models of hyperphagia: fasted C57BL/6J, ob/o b, and A(Y) mice, and mice injected with neuropeptide Y. Co-administra tion of the specific melanocortin antagonist and agouti-mimetic SHU911 9 completely blocked this inhibition. Furthermore, administration of S HU9119 significantly enhanced nocturnal feeding, or feeding stimulated by a prior fast. Our data show that melanocortinergic neurons exert a tonic inhibition of feeding behaviour. Chronic disruption of this inh ibitory signal is a likely explanation of the agouti obesity syndrome.