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A role for ghrelin in the central regulation of feeding

Abstract

Ghrelin is an acylated peptide that stimulates the release of growth hormone from the pituitary1. Ghrelin-producing neurons are located in the hypothalamus, whereas ghrelin receptors are expressed in various regions of the brain2,3,4, which is indicative of central—and as yet undefined—physiological functions. Here we show that ghrelin is involved in the hypothalamic regulation of energy homeostasis. Intracerebroventricular injections of ghrelin strongly stimulated feeding in rats and increased body weight gain. Ghrelin also increased feeding in rats that are genetically deficient in growth hormone. Anti-ghrelin immunoglobulin G robustly suppressed feeding. After intracerebroventricular ghrelin administration, Fos protein, a marker of neuronal activation5, was found in regions of primary importance in the regulation of feeding, including neuropeptide Y6 (NPY) neurons and agouti-related protein7 (AGRP) neurons. Antibodies and antagonists of NPY and AGRP abolished ghrelin-induced feeding. Ghrelin augmented NPY gene expression and blocked leptin-induced8 feeding reduction, implying that there is a competitive interaction between ghrelin and leptin in feeding regulation. We conclude that ghrelin is a physiological mediator of feeding, and probably has a function in growth regulation by stimulating feeding and release of growth hormone.

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Figure 1: Stimulation of feeding by single ICV administration of ghrelin.
Figure 2: Anti-ghrelin IgG suppresses feeding.
Figure 3: Effect of chronic ghrelin ICV administration on rats.
Figure 4: Localization of Fos expression in response to ICV administration of ghrelin.
Figure 5: Interactions of ghrelin with NPY, AGRP and leptin.

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Acknowledgements

We thank Y. Ueta for in situ hybridization; T. Kuroiwa, Y. Kawabata and R. Matsuura for assistance; and M. Ihara and A. Kanatani for providing L-152,804. This work was supported in part by grants-in-aid from the Ministry of Education, Science, Sports and Culture, and the Ministry of Health and Welfare, Japan, to M.N.

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Correspondence to Masamitsu Nakazato.

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Nakazato, M., Murakami, N., Date, Y. et al. A role for ghrelin in the central regulation of feeding. Nature 409, 194–198 (2001). https://doi.org/10.1038/35051587

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