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Resistance to the orexigenic effect of ghrelin in dietary-induced obesity in mice: reversal upon weight loss

International Journal of Obesity volume 28, pages 879–885 (2004)Cite this article

Abstract

BACKGROUND: Ghrelin, an endogenous ligand for growth hormone secretagogue receptor (GHS-R), is known to increase food intake in lean humans and rodents. In addition, ghrelin levels are increased by fasting in lean rodents and are elevated before meals in humans, suggesting an important role for ghrelin in meal initiation. However, in obese human, circulating ghrelin levels were found to be significantly reduced as compared to lean individuals.

OBJECTIVES: To evaluate whether circulating ghrelin levels, as well as ghrelin sensitivity, are decreased in obese individuals in order to limit its effect on food intake.

DESIGN: Lean C57BL/6J mice fed a chow, a low- (LFD) or a high-fat diet (HFD) were used to determine ghrelin regulation and secretion as well as ghrelin sensitivity.

MEASUREMENTS: Plasma ghrelin levels were measured in low- and high-fat fed mice. Ghrelin-induced food intake was measured in chow, low- and high-fat fed mice.

RESULTS: We measured ghrelin levels in lean and diet-induced obese mice, fed on an LFD or an HFD, respectively. We observed that not only ghrelin secretion was reduced in obese mice but its diurnal regulation was also lost. In addition, we failed to observe any change in ghrelin secretion upon fasting and refeeding. Moreover, we observed that the sensitivity to the orexigenic effects of exogenous ghrelin was reduced in obese mice when compared to lean mice fed a chow or a LFD. The insensitivity of obese mice to ghrelin was improved upon weigh loss.

CONCLUSION: Altogether, these results indicate that ghrelin secretion and regulation is impaired in dietary-induced obesity in mice and suggest that ghrelin inhibition could prevent weight regain after weight loss.

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Acknowledgements

We thank Biomedical Research Model (BRM), the Animal Resource Group (ARG) and Margarita Camara as well as Sandhya Punreddy for their technical assistance. We thank Paul Richardson from Abbott Laboratories (Abbott Park, IL, USA) for ghrelin peptide supply. Finally, we address a special thank to Eugene Bush and his team at Abbott Laboratories for their effort in developing the high-fat to low-fat switch model.

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  1. E Tozzo and A Stricker-Krongrad: E Tozzo and A Stricker-Krongrad contributed equally to this work.

Authors and Affiliations

  1. Metabolic Diseases Biology Department, Millennium Pharmaceuticals Inc., Cambridge, MA, USA

    M Perreault, N Istrate, L Wang, A J Nichols, E Tozzo & A Stricker-Krongrad

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  1. M Perreault
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Correspondence to M Perreault.

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Perreault, M., Istrate, N., Wang, L. et al. Resistance to the orexigenic effect of ghrelin in dietary-induced obesity in mice: reversal upon weight loss. Int J Obes 28, 879–885 (2004). https://doi.org/10.1038/sj.ijo.0802640

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