Changes in hypothalamic agouti-related protein (AGRP), but not alpha-MSH or pro-opiomelanocortin concentrations in dietary-obese and food-restricted rats

Melanocortin-4 receptor (MC4-R) density is thought to be regulated by synap tic availability of endogenous agonist, alpha-melanocyte-stimulating hormon e (alpha-MSH), and also by agouti-related protein (AGRP), which acts as a c ompetitive antagonist. As hypothalamic MC4-R have been implicated in the re gulation of energy balance, we examined concentrations of (alpha-MSH and AG RP in hypothalami of dietary-obese and food-restricted rats. In dietary-obe se rats, AGRP concentrations were significantly increased by 43% (p < 0.01) above lean controls, whereas a 91% (p < 0.01) reduction was observed in fo od-restricted rats. Surprisingly, hypothalamic concentrations of alpha-MSH and its precursor peptide, pro-opiomelanocortin (POMC), did not differ sign ificantly from controls in either model. In conclusion, we suggest that MC4 -R activity may not be regulated by changes in agonist (alpha-MSH) but by c hanges in the antagonist (AGRP) availability, which may modulate background activation of the receptor by tonic alpha-MSH release. AGRP may be an impo rtant modulator of feeding behaviour, (C) 1999 Academic Press.