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.

  • Review
  • Published:

Ghrelin and the growth hormone secretagogue receptor in growth and development

International Journal of Obesity volume 33, pages S48–S52 (2009)Cite this article

Abstract

The pancreas is a major source of ghrelin in the perinatal period, whereas gastric production progressively increases after birth. Loss of function of the genes for ghrelin or for the constitutively activated growth hormone secretagogue receptor (GHSR) does not affect birth weight and early postnatal growth. However, ghrl−/− or ghsr−/− mice fed a high fat diet starting soon after weaning are resistant to diet-induced obesity, suggesting that ghrelin affects the maturation of the metabolic axes involved in energy balance. In addition, animal and human studies suggest that GHSR plays a physiological role in linear growth. In mice, absence of the GHSR gene is associated with lower insulin-like growth factor 1 concentrations and lower body mass in adult animals, independently of food intake. In humans, a mutation of the GHSR gene that impairs the constitutive activity of the receptor was found in two families with short stature. Administration of acylated ghrelin to rat pups directly does not affect weight gain. In contrast, administration of ghrelin to pregnant or lactating rats results in greater fetal weight and postnatal weight gain, respectively, suggesting that maternal ghrelin may stimulate perinatal growth. These data point toward a physiological role for ghrelin and GHSR in growth and/or in the maturation of hormonal systems involved in the regulation of energy balance.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1

Similar content being viewed by others

References

  1. Zhu X, Cao Y, Voogd K, Steiner DF . On the processing of proghrelin to ghrelin. J Biol Chem 2006; 281: 38867–38870.

    Article  CAS  PubMed  Google Scholar 

  2. Ariyasu H, Takaya K, Tagami T, Ogawa Y, Hosoda K, Akamizu T et al. Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans. J Clin Endocrinol Metab 2001; 86: 4753–4758.

    Article  CAS  PubMed  Google Scholar 

  3. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K . Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999; 402: 656–660.

    Article  CAS  PubMed  Google Scholar 

  4. Sun Y, Wang P, Zheng H, Smith RG . Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor. Proc Natl Acad Sci USA 2004; 101: 4679–4684.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. van der Lely AJ, Tschöp M, Heiman ML, Ghigo E . Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr Rev 2004; 25: 426–457.

    Article  CAS  PubMed  Google Scholar 

  6. Holst B, Cygankiewicz A, Jensen TH, Ankersen M, Schwartz TW . High constitutive signaling of the ghrelin receptor—identification of a potent inverse agonist. Mol Endocrinol 2003; 17: 2201–2210.

    Article  CAS  PubMed  Google Scholar 

  7. Thompson NM, Gill DA, Davies R, Loveridge N, Houston PA, Robinson IC et al. Ghrelin and des-octanoyl ghrelin promote adipogenesis directly in vivo by a mechanism independent of the type 1a growth hormone secretagogue receptor. Endocrinology 2004; 145: 234–242.

    Article  CAS  PubMed  Google Scholar 

  8. Chanoine JP, Wong AC . Ghrelin gene expression is markedly higher in fetal pancreas compared with fetal stomach: effect of maternal fasting. Endocrinology 2004; 145: 3813–3820.

    Article  CAS  PubMed  Google Scholar 

  9. Chanoine JP, Wong AC, Barrios V . Obestatin, acylated and total ghrelin concentrations in the perinatal rat pancreas. Horm Res 2006; 66: 81–88.

    CAS  PubMed  Google Scholar 

  10. Hayashida T, Nakahara K, Mondal MS, Date Y, Nakazato M, Kojima M et al. Ghrelin in neonatal rats: distribution in stomach and its possible role. J Endocrinol 2002; 173: 239–245.

    Article  CAS  PubMed  Google Scholar 

  11. Walia P, Asadi A, Kieffer TJ, Johnson JD, Chanoine JP . Ontogeny of ghrelin, obestatin, preproghrelin, and prohormone convertases in rat pancreas and stomach. Pediatr Res 2008; e-pub ahead of print 3 September 2008.

  12. Heller RS, Jenny M, Collombat P, Mansouri A, Tomasetto C, Madsen OD et al. Genetic determinants of pancreatic epsilon-cell development. Dev Biol 2005; 286: 217–224.

    Article  CAS  PubMed  Google Scholar 

  13. Prado CL, Pugh-Bernard AE, Elghazi L, Sosa-Pineda B, Sussel L . Ghrelin cells replace insulin-producing beta cells in two mouse models of pancreas development. Proc Natl Acad Sci USA 2004; 101: 2924–2929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Farquhar J, Heiman M, Wong AC, Wach R, Chessex P, Chanoine JP . Elevated umbilical cord ghrelin concentrations in small for gestational age neonates. J Clin Endocrinol Metab 2003; 88: 4324–4327.

    Article  CAS  PubMed  Google Scholar 

  15. Wierup N, Svensson H, Mulder H, Sundler F . The ghrelin cell: a novel developmentally regulated islet cell in the human pancreas. Regul Pept 2002; 107: 63–69.

    Article  CAS  PubMed  Google Scholar 

  16. Wortley KE, Anderson KD, Garcia K, Murray JD, Malinova L, Liu R et al. Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel preference. Proc Natl Acad Sci USA 2004; 101: 8227–8232.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wortley KE, del Rincon JP, Murray JD, Garcia K, Iida K, Thorner MO et al. Absence of ghrelin protects against early-onset obesity. J Clin Invest 2005; 115: 3573–3578.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Chanoine JP, Yeung LP, Wong AC . Umbilical cord ghrelin concentrations in Asian and Caucasian neonates. Horm Res 2003; 60: 116–120.

    CAS  PubMed  Google Scholar 

  19. Pantel J, Legendre M, Cabrol S, Hilal L, Hajaji Y, Morisset S et al. Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature. J Clin Invest 2006; 116: 760–768.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS . A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 2001; 50: 1714–1719.

    Article  CAS  PubMed  Google Scholar 

  21. Tschop M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E, Heiman ML . Circulating ghrelin levels are decreased in human obesity. Diabetes 2001; 50: 707–709.

    Article  CAS  PubMed  Google Scholar 

  22. Grove KL, Cowley MA . Is ghrelin a signal for the development of metabolic systems? J Clin Invest 2005; 115: 3393–3397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Grove KL, Smith MS . Ontogeny of the hypothalamic neuropeptide Y system. Physiol Behav 2003; 79: 47–63.

    Article  CAS  PubMed  Google Scholar 

  24. Zigman JM, Nakano Y, Coppari R, Balthasar N, Marcus JN, Lee CE et al. Mice lacking ghrelin receptors resist the development of diet-induced obesity. J Clin Invest 2005; 115: 3564–3572.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. James RJ, Drewett RF, Cheetham TD . Low cord ghrelin levels in term infants are associated with slow weight gain over the first 3 months of life. J Clin Endocrinol Metab 2004; 89: 3847–3850.

    Article  CAS  PubMed  Google Scholar 

  26. Iniguez G, Ong K, Pena V, Avila A, Dunger D, Mericq V . Fasting and post-glucose ghrelin levels in SGA infants: relationships with size and weight gain at one year of age. J Clin Endocrinol Metab 2002; 87: 5830–5833.

    Article  CAS  PubMed  Google Scholar 

  27. Mackelvie KJ, Meneilly GS, Elahi D, Wong AC, Barr SI, Chanoine JP . Regulation of appetite in lean and obese adolescents after exercise: role of acylated and desacyl ghrelin. J Clin Endocrinol Metab 2007; 92: 648–654.

    Article  CAS  PubMed  Google Scholar 

  28. Stock S, Leichner P, Wong AC, Ghatei MA, Kieffer TJ, Bloom SR et al. Ghrelin, peptide YY, glucose-dependent insulinotropic polypeptide, and hunger responses to a mixed meal in anorexic, obese, and control female adolescents. J Clin Endocrinol Metab 2005; 90: 2161–2168.

    Article  CAS  PubMed  Google Scholar 

  29. Soriano-Guillen L, Barrios V, Campos-Barros A, Argente J . Ghrelin levels in obesity and anorexia nervosa: effect of weight reduction or recuperation. J Pediatr 2004; 144: 36–42.

    Article  CAS  PubMed  Google Scholar 

  30. Bittel DC, Butler MG . Prader–Willi syndrome: clinical genetics, cytogenetics and molecular biology. Expert Rev Mol Med 2005; 7: 1–20.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Haqq AM, Farooqi IS, O'Rahilly S, Stadler DD, Rosenfeld RG, Pratt KL et al. Serum ghrelin levels are inversely correlated with body mass index, age, and insulin concentrations in normal children and are markedly increased in Prader–Willi syndrome. J Clin Endocrinol Metab 2003; 88: 174–178.

    Article  CAS  PubMed  Google Scholar 

  32. DelParigi A, Tschöp M, Heiman ML, Salbe AD, Vozarova B, Sell SM et al. High circulating ghrelin: a potential cause for hyperphagia and obesity in Prader–Willi syndrome. J Clin Endocrinol Metab 2002; 87: 5461–5464.

    Article  CAS  PubMed  Google Scholar 

  33. Cummings DE, Clement K, Purnell JQ, Vaisse C, Foster KE, Frayo RS et al. Elevated plasma ghrelin levels in Prader Willi syndrome. Nat Med 2002; 8: 643–644.

    Article  CAS  PubMed  Google Scholar 

  34. De Waele K, Ishkanian SL, Bogarin R, Miranda CA, Ghatei MA, Stephen R et al. Long-acting octreotide treatment causes a sustained decrease in ghrelin concentrations but does not affect weight, behaviour and appetite in subjects with Prader Willi syndrome. Eur J Endocrinol 2008; 159: 381–388.

    Article  CAS  PubMed  Google Scholar 

  35. Nakahara K, Nakagawa M, Baba Y, Sato M, Toshinai K, Date Y et al. Maternal ghrelin plays an important role in rat fetal development during pregnancy. Endocrinology 2006; 147: 1333–1342.

    Article  CAS  PubMed  Google Scholar 

  36. Nakahara K, Hayashida T, Nakazato M, Kojima M, Hosoda H, Kangawa K et al. Effect of chronic treatments with ghrelin on milk secretion in lactating rats. Biochem Biophys Res Commun 2003; 303: 751–755.

    Article  CAS  PubMed  Google Scholar 

  37. Tham E, Liu J, Gaylinn B, Thorner M, Thompson D, Chanoine J-P . Acyl and des-acyl ghrelin concentrations during pregnancy and early postpartum in women with and without gestational diabetes. Can J Diabetes 2007; 31: 269 (OR 45).

    Google Scholar 

Download references

Acknowledgements

This work was supported in part by Grant MOP 81291 of the Canadian Institutes of Health and Research (CIHR).

Author information

Authors and Affiliations

  1. Department of Pediatrics, Endocrinology and Diabetes Unit, British Columbia's Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada

    J-P Chanoine, K De Waele & P Walia

Authors
  1. J-P Chanoine
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K De Waele
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P Walia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J-P Chanoine.

Additional information

Conflict of interest

J-P Chanoine has received consulting fees from Novo Nordisk and Nestle as well as lecture fees from Roche. K De Waele and P Walia have declared no financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chanoine, JP., De Waele, K. & Walia, P. Ghrelin and the growth hormone secretagogue receptor in growth and development. Int J Obes 33 (Suppl 1), S48–S52 (2009). https://doi.org/10.1038/ijo.2009.17

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2009.17

Keywords

This article is cited by

Search

Advanced search

Quick links