EVIDENCE THAT OREXIGENIC EFFECTS OF MELANOCORTIN-4 RECEPTOR ANTAGONIST HS014 ARE MEDIATED BY NEUROPEPTIDE-Y

Recent studies using melanocortin-4 receptor (MC4R) knockout mice and MC4R antagonists have shown that weakening of MC4R-ergic tone increase s food intake and causes obesity. In this study, we used the newly dis covered selective MC4R antagonist HS014 for increasing food intake in free-feeding rats and evaluated the effects of the NPY Y-1 receptor an tagonist 1229U91 and the selective serotonin uptake inhibitor fluoxeti ne on this increased feeding behavior. 1229U91 (12 nmol, i.c.v.), whic h alone does not affect food intake, significantly attenuated the orex igenic effects of HS014, whereas 1 and 3 nmol doses of 1229U91 were in effective. Fluoxetine, which has been shown to inhibit NPY release, in hibited spontaneous food intake and completely blocked the stimulation of food intake by HS014, These data suggest that feeding induced by w eakening of the MC4R-ergic tone may be mediated through activation of the NPY-ergic system. This is the first report showing that physiologi cal feeding response evoked by MC4R blockage is influenced by NPY sign alling. (C) 1998 Academic Press.