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

Abstract

OBJECTIVE:The role of the melanocortin system in the feeding effects of peripheral peptide YY ) 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 (a-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 mmol/kg), NDP-a-MSH (0.2 mmol/kg), leptin (2 mmol/kg) (all 24 h fasted state) and ghrelin (0.2 mmol/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), agematched 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-a-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 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 , a-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.

Xenin, a Gastrointestinal Peptide, Regulates Feeding Independent of the Melanocortin Signaling Pathway

“…Ghrelin stimulates food intake by interacting with melanocortins, and the orexigenic effect of ghrelin is abolished in mice lacking both AGRP and neuropeptide Y (24,26). In contrast, the anorectic effects of glucagon-like peptide-1 and peptide YY are independent of the melanocortin signaling pathway (27)(28)(29). Because xenin activated the hypothalamus, as measured by c-fos mRNA expression and Fos immunoreactivity, we wished to determine whether xenin-induced anorexia involves central melanocortin signaling.…”

Abnormalities of the somatotrophic axis in the obese agouti mouse

“…27 The assay detected changes of 25 pmol/l of plasma ghrelin with 95% confidence limit, with an interassay coefficient of variation 5.5%.…”

Ghrelin increases food intake in obese as well as lean subjects

“…[27][28][29] The assay crossreacts fully (100%) with both octanoyl and des octanoyl ghrelin and did not crossreact with any known gastrointestinal or pancreatic peptide hormones. The antisera (SC-10368) was obtained from Santa Cruz biotechnology and used at a final dilution of 1:50 000.…”