Ghrelin induces adiposity in rodents (original) (raw)

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.

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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

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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.

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  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

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  1. Matthias Tschöp
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  2. David L. Smiley
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  3. Mark L. Heiman
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Correspondence toMatthias Tschöp.

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

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