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A role for ghrelin in the central regulation of feeding

Nature volume 409, pages 194–198 (2001)Cite this article

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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References

  1. Kojima, M. et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402, 656–660 (1999).

    Article  CAS  ADS  Google Scholar 

  2. Howard, A. D. et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 273, 974 –977 (1996).

    Article  CAS  ADS  Google Scholar 

  3. McKee, K. K. et al. Molecular analysis of rat pituitary and hypothalamic growth hormone secretagogue receptors. Mol. Endocrinol. 11 , 415–423 (1997).

    Article  CAS  Google Scholar 

  4. Guan, X. M. et al. Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Mol. Brain Res. 48, 23–29 (1997).

    Article  CAS  Google Scholar 

  5. Sagar, S. M., Sharp, F. R. & Curran, T. Expression of c-fos protein in brain: metabolic mapping at the cellular level. Science 240, 1328–1331 (1988).

    Article  CAS  ADS  Google Scholar 

  6. Stanley, B. G., Kyrkouli, S. E., Lampert, S. & Leibowitz, S. F. Neuropeptide Y chronically injected into the hypothalamus: a powerful neurochemical inducer of hyperphagia and obesity. Peptides 7, 1189–1192 (1986).

    Article  CAS  Google Scholar 

  7. Hahn, T., Breininger, J., Baskin, D. & Schwartz, M. Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons. Nature Neurosci. 1, 271–272 (1998).

    Article  CAS  Google Scholar 

  8. Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).

    Article  CAS  ADS  Google Scholar 

  9. Bowers, C. Y., Momany, F. A., Reynolds, G. A. & Hong, A. On the in vitro and in vivo activity of a new synthetic hexapeptide that acts on the pituitary to specifically release growth hormone. Endocrinology 114, 1537–1545 (1984).

    Article  CAS  Google Scholar 

  10. Locke, W., Kirgis, H. D., Bowers, C. Y. & Abdoh, A. A. Intracerebroventricular growth-hormone-releasing peptide-6 stimulates eating without affecting plasma growth hormone responses in rats. Life Sci. 56, 1347–1352 ( 1995).

    Article  CAS  Google Scholar 

  11. Cheng, K. et al. The synergistic effects of His-d-Trp-Ala-Trp-d-Phe-Lys-NH 2 on growth hormone (GH)-releasing factor-stimulated GH release and intracellular adenosine 3′,5′-monophosphate accumulation in rat primary pituitary cell culture. Endocrinology 124, 2791–2798 (1989).

    Article  CAS  Google Scholar 

  12. Okuma, S. & Kawashima, S. Spontanenous dwarf rat. Exp. Anim. 29, 301–304 ( 1980).

    Google Scholar 

  13. Takeuchi, T. et al. Molecular mechanism of growth hormone (GH) deficiency in the spontaneous dwarf rat: detection of abnormal splicing of GH messenger ribonucleic acid by the polymerase chain reaction. Endocrinology 126, 31–38 (1990).

    Article  CAS  Google Scholar 

  14. Schwartz, M. W. et al. Identification of targets of leptin action in rat hypothalamus. J. Clin. Invest. 98, 1101– 1106 (1996).

    Article  CAS  Google Scholar 

  15. Mercer, J. G. et al. Coexpression of leptin receptor and preproneuropeptide Y mRNA in arcuate nucleus of mouse hypothalamus. J. Neuroendocrinol. 8, 733–735 (1996).

    Article  CAS  Google Scholar 

  16. Broberger, C. et al. The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice. Proc. Natl Acad. Sci. USA 95, 15043– 15048 (1998).

    Article  CAS  ADS  Google Scholar 

  17. Schwartz, M. W. et al. Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus. Diabetes 46, 2119–2123 (1997).

    Article  CAS  Google Scholar 

  18. Kristensen, P. et al. Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature 393, 72– 76 (1998).

    Article  CAS  ADS  Google Scholar 

  19. Willesen, M. G., Kristensen, P. & Romer, J. Co-localization of growth hormone secretagogue receptor and NPY mRNA in the arcuate nucleus of the rat. Neuroendocrinology 70, 306–316 ( 1999).

    Article  CAS  Google Scholar 

  20. Dickson, S. L. & Luckman, S. M. Induction of c-fos messenger ribonucleic acid in neuropeptide Y and growth hormone (GH)-releasing factor neurons in the rat arcuate nucleus following systemic injection of the GH secretagogue, GH-releasing peptide-6. Endocrinology 138, 771–777 ( 1997).

    Article  CAS  Google Scholar 

  21. Honda, K. et al. An electrophysiological and morphological investigation of the projections of growth hormone-releasing peptide-6-responsive neurons in the rat arcuate nucleus to the median eminence and to the paraventricular nucleus. Neuroscience 90, 875–883 (1999).

    Article  CAS  Google Scholar 

  22. Gerald, C. et al. A receptor subtype involved in neuropeptide-Y-induced food intake. Nature 382, 168– 171 (1996).

    Article  CAS  ADS  Google Scholar 

  23. Wieland, H. A. et al. Subtype selectivity of the novel nonpeptide neuropeptide Y Y1 receptor antagonist BIBO 3304 and its effect on feeding in rodents. Br. J. Pharmacol. 125, 549–555 (1998).

    Article  CAS  Google Scholar 

  24. Cone, R. D. et al. The melanocortin receptors: agonists, antagonists, and the hormonal control of pigmentation. Rec. Prog. Horm. Res. 51, 287–317 (1996).

    CAS  PubMed  Google Scholar 

  25. Stephens, T. W. et al. The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature 377, 530– 532 (1995).

    Article  CAS  ADS  Google Scholar 

  26. Schwartz, M. W. et al. Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice. Diabetes 45, 531–535 ( 1996).

    Article  CAS  Google Scholar 

  27. Yamamoto, Y. et al. Down regulation of the prepro-orexin gene expression in genetically obese mice. Mol. Brain Res. 65, 14– 22 (1999).

    Article  CAS  Google Scholar 

  28. Ida, T., Nakahara, K., Murakami, N. & Nakazato, M. Effects of lateral cerebroventricular injection of the appetite-stimulating neuropeptides, orexin and neuropeptide Y, on the various behavioral activities of rats. Brain Res. 821, 526– 529 (1999).

    Article  CAS  Google Scholar 

  29. Daniels, A. J. et al. High-affinity neuropeptide Y receptor antagonists. Proc. Natl Acad. Sci. USA 92, 9067– 9071 (1995).

    Article  CAS  ADS  Google Scholar 

  30. Kanatani, A. et al. L-152,804: orally active and selective neuropeptide Y Y5 receptor antagonist. Biochem. Biophys. Res. Commun. 272, 169-173 (2000).

    Article  Google Scholar 

  31. Murakami, N., Marumoto, N., Nakahara, K. & Murakami, T. Daily injections of melatonin entrain the circadian activity rhythms of nocturnal rats but not diurnal chipmunks. Brain Res. 775, 240–243 (1997).

    Article  CAS  Google Scholar 

  32. Date, Y. et al. Orexin, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems. Proc. Natl Acad. Sci. USA 96, 748–753 ( 1999).

    Article  CAS  ADS  Google Scholar 

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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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Authors and Affiliations

  1. Third Department of Internal Medicine Miyazaki Medical College, Kiyotake, Miyazaki, 889-1692 , Japan

    Masamitsu Nakazato, Yukari Date & Shigeru Matsukura

  2. Department of Veterinary Physiology Miyazaki University, Miyazaki, 889-2192, Japan

    Noboru Murakami

  3. Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka, 565-8565 , Japan

    Masayasu Kojima, Hisayuki Matsuo & Kenji Kangawa

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  1. Masamitsu Nakazato
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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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