The melanocortinergic neurons located in the arcuate nucleus and the nucleus of the solitary tract project to a number of hypothalamic nuclei, including paraventricular nucleus, lateral hypothalamic area, dorso- and ventromediate hypothalamic nucleus, which are known to be important in regulation of feeding behavior. The melanocortinergic receptor MC3-R and MC4-R have also be identified at these sites. These neuroanatomic data suggest that the melanocortinergic pathways are involved in the regulation of feeding. The agouti obesity syndrome is caused by expression of the agouti peptide outside its normal site in the skin; agouti is also a potent antagonist of the MC4-R. The "melanocortin hypothesis" proposed that agouti causes obesity by antagonism of the hypothalamic MC4-R. To test this, we centrally administered the cyclic melanocortin analogues. MTII a potent agonist of MC4-R (EC50=0.057±0.024 nM) and MC3-R (EC50=0.27±0.23 nM), SHU9119, a potent antagonist of MC4-R (IC50=0.36±0.13 nM) and less potent antagonist of MC3-R (IC50=4.5±2.1 nM), and observed their effects on feeding behavior. Intracerebroventricular (ICV) administration of MTII produced a dose-responsive inhibition of food intake in 16 hr fasted C57BL/6J mice with an IC50 of 0.6 nmol at the 2 hr point after drug administration. This inhibition of feeding could be completely blocked by coadministration of SHU9119. MTII also inhibited feeding in three other models of hyperphagia, ob/oh, A, and Neuropeptide Y-injected mice. ICV injection of γ2-MSH, which only activated MC3-R, failed to inhibit feeding in fasted C57BL/6J mice. Furthermore, ICV administration of SHU9119 enhanced nocturnal feeding in mice fed ad libitum, and daytime feeding in fasted animals. The data show that melanocortinergic neurons may exert a tonic inhibition of feeding through MC4-R. Chronic disruption of this inhibitory signal is a likely explanation of the agouti obesity syndrome. (Funded by NIDDK & NICHD. RDC. NIDDK. VJH, BAB. RAK.).
|Original language||English (US)|
|State||Published - 1997|
ASJC Scopus subject areas
- Molecular Biology