Pre-obese and obese agouti mice are sensitive to the anorectic effects of peptide YY3-36 but resistant to ghrelin

OBJECTIVE: The role of the melanocortin system in the feeding effects of peripheral peptide YY3-36 (PYY3-36) and ghrelin was investigated using the agouti (A(y)/a) mouse as a model of abnormal melanocortin signalling. Furthermore, we examined whether the ectopic expression of agouti protein in A(y)/a mice results in complete MC4-R inhibition, by studying the effects of peripheral alpha-melanocyte-stimulating hormone (alpha-MSH) and leptin on food intake. DESIGN: Adult A(y)/a mice were studied in the pre-obese state ( 7 - 8 weeks) and obese state (14 - 15 weeks). Animals received PYY3-36 (0.02 mumol/kg), NDP-alpha-MSH (0.2 mumol/kg), leptin (2 mumol/kg) ( all 24 h fasted state) and ghrelin (0.2 mumol/kg) (fed state) by intraperitoneal (i.p.) injection. Age-matched A(y)/a controls received i.p. saline. A separate cohort of wild-type (WT), age-matched controls received the same peptide dose or saline. Food intake was measured at 1, 2, 4, 8 and 24 h post-injection and compared in all four groups. Plasma leptin-, ghrelin- and PYY-like immunoreactivity (IR) were measured using radioimmunoassay (RIA). RESULTS: At 2 h post-injection, PYY3-36 reduced food intake in pre-obese and obese A(y)/a mice, whereas ghrelin had no effect. Plasma ghrelin levels were significantly reduced in pre-obese and obese A(y)/a mice compared to WT controls. Peripheral administration of NDP-alpha-MSH and leptin acutely suppressed feeding (0 - 2 h) in pre-obese and obese A(y)/a mice. CONCLUSIONS: Responsiveness of pre-obese and obese A(y)/a mice to PYY3-36 suggests that the melanocortin system may not be essential for the anorectic effects of this peptide. Melanocortinergic antagonism by agouti protein in A(y)/a mice may be sufficient to block the effects of endogenous, but not exogenous PYY3-36, alpha-MSH and leptin. The mechanism underlying ghrelin resistance in A(y)/a mice may result from antagonism of hypothalamic melanocortin receptors-4 by agouti protein, supporting a role for the melanocortin system in mediating ghrelin's actions.