OBJECTIVE: The role of the melanocortin system in the feeding effects of peripheral peptide YY 3–36 (PYY 3–36) 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 (α-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 PYY 3–36 (0.02 μmol/kg), NDP-α-MSH (0.2 μmol/kg), leptin (2 μmol/kg)(all 24 h fasted state) and ghrelin (0.2 μmol/kg)(fed state) by intraperitoneal (ip) injection. Age-matched A y/a controls received ip 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, PYY 3–36 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-α-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 PYY 3–36 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 PYY 3–36, α-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.