Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Ghrelin induces adiposity in rodents

Nature volume 407, pages 908–913 (2000)Cite this article

Abstract

The discovery of the peptide hormone ghrelin, an endogenous ligand for the growth hormone secretagogue (GHS) receptor1,2, yielded the surprising result3 that the principal site of ghrelin synthesis is the stomach and not the hypothalamus. Although ghrelin is likely to regulate pituitary growth hormone (GH) secretion3,4 along with GH-releasing hormone and somatostatin, GHS receptors have also been identified on hypothalamic neurons5 and in the brainstem6. Apart from potential paracrine effects, ghrelin may thus offer an endocrine link between stomach, hypothalamus and pituitary, suggesting an involvement in regulation of energy balance. Here we show that peripheral daily administration of ghrelin caused weight gain by reducing fat utilization in mice and rats. Intracerebroventricular administration of ghrelin generated a dose-dependent increase in food intake and body weight. Rat serum ghrelin concentrations were increased by fasting and were reduced by re-feeding or oral glucose administration, but not by water ingestion. We propose that ghrelin, in addition to its role in regulating GH secretion, signals the hypothalamus when an increase in metabolic efficiency is necessary.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Ghrelin-stimulated adiposity in mice.
Figure 2: Differential effects of ghrelin and growth hormone on respiratory quotient (RQ) and energy expenditure (EE) in mice.
Figure 3: Ghrelin induced a positive energy balance in dwarf rats deficient in growth hormone.
Figure 4: Central effects of ghrelin on energy balance in adult male Sprague–Dawley rats.
Figure 5: Circulating ghrelin levels respond to feeding state in adult male Sprague–Dawley rats.

Similar content being viewed by others

References

  1. 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 

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

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  4. Hosoda, H., Kojima, M., Matsuo, H. & Kangawa, K. Purification and characterization of rat des-Gln14-ghrelin, a second endogenous ligand for the growth hormone secretagogue receptor. J. Biol. Chem. 275, 21995–22000 (2000).

    Article  CAS  Google Scholar 

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

    CAS  Google Scholar 

  6. Bailey, A. R., Von Englehardt, N., Leng, G., Smith, R. G. & Dickson, S. L. Growth hormone secretagogue activation of the arcuate nucleus and brainstem occurs via a non-noradrenergic pathway. J. Neuroendocrinol. 12, 191– 197 (2000).

    Article  CAS  Google Scholar 

  7. Scheurink, A. J., Leuvenink, H., Benthem, B. & Steffens, A. B. Dexfenfluramine treatment influences plasma catecholamines and energy substrate metabolism in rats. Physiol. Behav. 53, 879–887 (1993).

    Article  CAS  Google Scholar 

  8. Snitker, S., Tataranni, P. A. & Ravussin, E. Respiratory quotient is inversely associated with muscle sympathetic nerve activity. J. Clin. Endocrinol. Metab. 83, 3977–3979 (1998).

    Article  CAS  Google Scholar 

  9. Atrens, D. M., Sinden, J. D., Penicaud, L., Devos, M. & Le Magnen, J. Hypothalamic modulation of energy expenditure. Physiol. Behav. 35, 15– 20 (1985).

    Article  CAS  Google Scholar 

  10. Kuriyama, H., Hotta, M., Wakabayashi, I. & Shibasaki, T. A 6-day intracerebroventricular infusion of the growth hormone-releasing peptide KP-102 stimulates food intake in both non-stressed and intermittently-stressed rats. Neurosci. Lett. 282, 109– 112 (2000).

    Article  CAS  Google Scholar 

  11. Okada, K. et al. Intracerebroventricular administration of the growth hormone-releasing peptide KP-102 increases food intake in free-feeding rats. Endocrinology 137, 5155–5158 ( 1996).

    Article  CAS  Google Scholar 

  12. Salomon, F., Cuneo, R. C., Hesp, R. & Sonksen, P. H. The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N. Engl. J. Med. 321, 1797–1803 ( 1989).

    Article  CAS  Google Scholar 

  13. Vernon, R. G. GH inhibition of lipogenesis and stimulation of lipolysis in sheep adipose tissue: involvement of protein serine phosphorylation and dephosphorylation and phospholipase C. J. Endocrinol. 150, 129–140 (1996).

    Article  CAS  Google Scholar 

  14. Charlton, H. M. et al. Growth hormone-deficient dwarfism in the rat: a new mutation. J. Endocrinol. 119, 51– 58 (1988).

    Article  CAS  Google Scholar 

  15. 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 

  16. Bailey, A. R. et al. Chronic central infusion of growth hormone secretagogues: effects on fos expression and peptide gene expression in the rat arcuate nucleus. Neuroendocrinology 70, 83– 92 (1999).

    Article  CAS  Google Scholar 

  17. Luckman, S. M., Rosenzweig, I. & Dickson, S. L. Activation of arcuate nucleus neurons by systemic administration of leptin and growth hormone-releasing peptide-6 in normal and fasted rats. Neuroendocrinology 70, 93–100 (1999).

    Article  CAS  Google Scholar 

  18. Erickson, J. C., Clegg, K. E. & Palmiter, R. D. Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y. Nature 381, 415–421 (1996).

    Article  ADS  CAS  Google Scholar 

  19. Chen, Y. & Heiman, M. L. Chronic leptin administration promotes lipid utilization until fat mass is greatly reduced and preserves lean mass of normal female rats. Regul. Pept. (in the press).

  20. Elia, M. & Livesey, G. Energy expenditure and fuel selection in biological systems: the theory and practice of calculations based on indirect calorimetry and tracer methods. World Rev. Nutr. Diet 70, 68–131 (1992).

    Article  CAS  Google Scholar 

  21. Flatt, J. P. Assessment of daily and cumulative carbohydrate and fat balances in mice. J. Nutr. Biochem. 2, 193– 202 (1991).

    Article  CAS  Google Scholar 

  22. Rose, B. S., Flatt, W. P., Martin, R. J. & Lewis, R. D. Whole body composition of rats determined by dual energy X-ray absorptiometry is correlated with chemical analysis. J. Nutr. 128, 246–250 (1998).

    Article  CAS  Google Scholar 

  23. Hsiung, H. M. & MacKellar, W. C. Expression of bovine growth hormone derivatives in Escherichia coli and the use of the derivatives to produce natural sequence growth hormone by cathepsin C cleavage. Methods Enzymol. 153, 390–401 (1987).

    Article  CAS  Google Scholar 

  24. Heiman, M. L., Nekola, M. V., Murphy, W. A., Lance, V. A. & Coy, D. H. An extremely sensitive in vitro model for elucidating structure-activity relationships of growth hormone-releasing factor analogs. Endocrinology 116, 410– 415 (1985).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J. Caro, G. Cutler Jr, E. Ravussin, R. Al-Awar, C.J. Strasburger and A. Tashjian Jr for critical review, R. Palmiter for providing NPY-deficient mice and L. Craft, J. Baker, J. Bridwell, J. Jacobs, W.T. Johnson, P. Surface, F. Tinsley and T. Butler for technical assistance.

Author information

Authors and Affiliations

  1. A Division of Eli Lilly and Company, Endocrine Research and BioResearch Technologies & Proteins Lilly Research Laboratories, Lilly Corporate Center, Drop Code 0545, Indianapolis, 46285, Indiana, USA

    Matthias Tschöp, David L. Smiley & Mark L. Heiman

Authors
  1. Matthias Tschöp
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David L. Smiley
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mark L. Heiman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Matthias Tschöp.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tschöp, M., Smiley, D. & Heiman, M. Ghrelin induces adiposity in rodents. Nature 407, 908–913 (2000). https://doi.org/10.1038/35038090

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35038090

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing