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

International Journal of Obesity volume 28, pages 886–893 (2004)Cite this article

Abstract

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 (Ay/a) mouse as a model of abnormal melanocortin signalling. Furthermore, we examined whether the ectopic expression of agouti protein in Ay/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 Ay/a mice were studied in the pre-obese state (7–8 weeks) and obese state (14–15 weeks). Animals received PYY3–36 (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 (i.p.) injection. Age-matched Ay/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 Ay/a mice, whereas ghrelin had no effect. Plasma ghrelin levels were significantly reduced in pre-obese and obese Ay/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 Ay/a mice.

CONCLUSIONS: Responsiveness of pre-obese and obese Ay/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 Ay/a mice may be sufficient to block the effects of endogenous, but not exogenous PYY3–36, α-MSH and leptin. The mechanism underlying ghrelin resistance in Ay/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.

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Acknowledgements

We thank K Murphy, K Smith and A Wren for their helpful comments while reading this manuscript. NMM is a Wellcome Trust Clinical Training Fellow. This work is supported by an MRC programme Grant G7811974 (Bloom, Ghatei and Small).

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  1. Department of Metabolic Medicine, Imperial College, Hammersmith Campus, London, UK

    N M Martin, C J Small, A Sajedi, M Patterson, M A Ghatei & S R Bloom

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Correspondence to S R Bloom.

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Martin, N., Small, C., Sajedi, A. et al. Pre-obese and obese agouti mice are sensitive to the anorectic effects of peptide YY3–36 but resistant to ghrelin. Int J Obes 28, 886–893 (2004). https://doi.org/10.1038/sj.ijo.0802646

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