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Is there altered sensitivity to ghrelin-receptor ligands in leptin-deficient mice?: importance of satiety state and time of day

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Abstract

Background

Several fine-tuned and interconnected hypothalamic peptidergic systems orchestrate the regulation of energy homeostasis in the body. The orexigenic peptide ghrelin and the anorexigenic peptide leptin are among the most important, and both have been implicated in the development of eating disorders from obesity to anorexia nervosa.

Objectives

The goal of these studies was to examine the response of leptin-deficient ob/ob mice in ghrelin-receptor ligands in a food intake task.

Methods

Changes in cumulative food intake were measured after peripheral administration of ghrelin (1 and 2 nmol/10 g) and the ghrelin-receptor antagonist (D-Lys3)-GHRP-6 (66.6 and 133.3 nmol/10 g) in obese and lean control mice during the light and dark cycle as well as in a state of food restriction. Hypothalamic ghrelin and ghrelin-receptor expression was measured in ob/ob and lean mice at two different timepoints.

Results

Ghrelin increased food intake in lean and obese mice in the light and dark cycle, whereas the ghrelin-receptor antagonist caused significantly stronger reduction in food intake in obese mice only in the dark cycle. After fasting, ob/ob mice displayed decreased light cycle sensitivity to the anorexigenic effects of the ghrelin-receptor antagonist. Hypothalamic expression levels of ghrelin were unaltered during the light cycle but decreased during the dark cycle in ob/ob mice; whereas, although unchanged in the light cycle, ghrelin-receptor expression was increased in the dark cycle in obese mice.

Conclusion

The functionality and sensitivity of the ghrelinergic system is dependent on the time of day and the satiety state in leptin-deficient ob/ob mice.

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Acknowledgements

The authors would like to thank Caroline Brown and Kieran Davey for their excellent technical assistance. The work described herein was supported by Enterprise Ireland under Grant Number CC20080001. The Alimentary Pharmabiotic Centre is a research centre funded by Science Foundation Ireland (SFI), through the Irish Government's National Development Plan. The authors and their work were supported by SFI (grant no.s 02/CE/B124 and 07/CE/B1368). The centre is also funded by GlaxoSmithKline. JFC is funded by European Community's Seventh Framework Programme; Grant Number: FP7/2007-2013, Grant Agreement 201714.

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Authors and Affiliations

  1. School of Pharmacy, Cavanagh Pharmacy Building, University College Cork, Cork, Ireland

    Beate C. Finger, Harriët Schellekens & John F. Cryan

  2. Food for Health Ireland, University College Cork, Cork, Ireland

    Beate C. Finger, Harriët Schellekens, Timothy G. Dinan & John F. Cryan

  3. Department of Psychiatry, University College Cork, Cork, Ireland

    Timothy G. Dinan

  4. Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland

    John F. Cryan

  5. Laboratory of NeuroGastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland

    Timothy G. Dinan & John F. Cryan

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  1. Beate C. Finger
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  2. Harriët Schellekens
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  3. Timothy G. Dinan
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  4. John F. Cryan
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Correspondence to John F. Cryan.

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Finger, B.C., Schellekens, H., Dinan, T.G. et al. Is there altered sensitivity to ghrelin-receptor ligands in leptin-deficient mice?: importance of satiety state and time of day. Psychopharmacology 216, 421–429 (2011). https://doi.org/10.1007/s00213-011-2234-3

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  • DOI: https://doi.org/10.1007/s00213-011-2234-3

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