Skip to main content
SpringerLink
Log in

Feeding behavior during long-term hexarelin administration in young and old rats

  • Original Articles
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Ghrelin, a 28-amino-acid peptide isolated from the stomach, is the natural ligand of the GH-secretagogues receptor-1a (GHS-R1a) and, so far, the only discovered circulating appetite-stimulating hormone. Similarly to ghrelin, many synthetic compounds belonging to the GHS family stimulate both GH secretion and feeding, whereas some stimulate GH secretion only. In the past years, studies have focused on the potential of the GHS to stimulate GH release during long-term treatment in humans and experimental animals. Few data are available about the extraendocrine effects of the GHS during several weeks of treatment, particularly in old rats. The aim of the present study was first to identify the lowest dose of hexarelin giving maximal stimulation of food intake both in young (3-month-old) and old rats (24-month-old). A dose-response study (80–320 µg/kg, sc) revealed that hexarelin at the dose of 80 µg/kg gave reproducibly maximal stimulation of food consumption in young as well as in old rats. Second, we evaluated the effect of 8-week daily sc treatment with hexarelin in young and old male rats. The outcome of the chronic study was that hexarelin (80 µg/kg, sc, once daily) maintained a persistent significant orexigenic action throughout the treatment period, both in young and old rats. Interestingly, hexarelin treatment did not affect body weight gain either in young or old rats. We conclude that hexarelin is endowed with long-lasting orexigenic activity and might represent a potential therapeutic approach for pathological conditions characterized by a decline in food intake.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. van der Lely AJ, Tschöp M, Heiman ML, Ghigo E. Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr Rev 2004, 25: 426–57.

    Article  PubMed  CAS  Google Scholar 

  2. Tschöp M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature 2000, 407: 908–13.

    Article  PubMed  Google Scholar 

  3. Wren AM, Small CJ, Ward HL, et al. The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology 2000, 141: 4325–8.

    Article  PubMed  CAS  Google Scholar 

  4. Wren AM, Small CJ, Abbott CR, et al. Ghrelin causes hyperphagia and obesity in rats. Diabetes 2001, 50: 2540–7.

    Article  PubMed  CAS  Google Scholar 

  5. Wren AM, Seal LJ, Cohen MA, et al. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 2001, 86: 5992.

    Article  PubMed  CAS  Google Scholar 

  6. Torsello A, Luoni M, Schweiger F, et al. Novel hexarelin analogs stimulate feeding in the rat through a mechanism not involving growth hormone release. Eur J Pharmacol 1998, 360: 123–9.

    Article  PubMed  CAS  Google Scholar 

  7. Torsello A, Locatelli V, Melis MR, et al. Differential orexigenic effects of hexarelin and its analogs in the rat hypothalamus: indication for multiple growth hormone secretagogue receptor subtypes. Neuroendocrinology 2000, 72: 327–32.

    Article  PubMed  CAS  Google Scholar 

  8. Ghigo E, Arvat E, Gianotti L, et al. Growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, after intravenous, subcutaneous, intranasal, and oral administration in man. J Clin Endocrinol Metab 1994, 78: 693–8.

    PubMed  CAS  Google Scholar 

  9. Cella SG, Cerri CG, Daniel S, et al. Sixteen weeks of hexarelin therapy in old dogs: effects on the somatotropic axis, muscle morphology, and bone metabolism. J Gerontol A Biol Sci Med Sci 1996, 51: B439–47.

    Article  PubMed  CAS  Google Scholar 

  10. Ghigo E, Arvat E, Gianotti L, et al. Short-term administration of intranasal or oral Hexarelin, a synthetic hexapeptide, does not desensitize the growth hormone responsiveness in human aging. Eur J Endocrinol 1996, 135: 407–12.

    Article  PubMed  CAS  Google Scholar 

  11. Rahim A, O’Neill PA, Shalet SM. Growth hormone status during long-term hexarelin therapy. J Clin Endocrinol Metab 1998, 83: 1644–9.

    Article  PubMed  CAS  Google Scholar 

  12. Matsumoto AM, Marck BT, Gruenewald DA, Wolden-Hanson T, Naai MA. Aging and the neuroendocrine regulation of reproduction and body weight. Exp Gerontol 2000, 35: 1251–65.

    Article  PubMed  CAS  Google Scholar 

  13. Sullivan DH. The role of nutrition in increased morbidity and mortality. Clin Geriatr Med 1995, 11: 661–74.

    PubMed  CAS  Google Scholar 

  14. Morley JE. Anorexia of aging: physiologic and pathologic. Am J Clin Nutr 1997, 66: 760–73.

    PubMed  CAS  Google Scholar 

  15. Rigamonti AE, Cella SG, Marazzi N, Muller EE. Six-week treatment with hexarelin in young dogs: evaluation of the GH responsiveness to acute hexarelin or GHRH administration, and of the orexigenic effect of hexarelin. Eur J Endocrinol 1999, 141: 313–20.

    Article  PubMed  CAS  Google Scholar 

  16. Torsello A, Luoni M, Grilli R, et al. Hexarelin stimulation of growth hormone release and mRNA levels in an infant and adult rat model of impaired GHRH function. Neuroendocrinology 1997, 65: 91–7.

    Article  PubMed  CAS  Google Scholar 

  17. Cattaneo L, Luoni M, Settembrini B, Müller EE, Cocchi D. Effect of long-term administration of Hexarelin on the somatotrophic axis in old rats. Pharmacol Res 1997, 36: 49–54.

    Article  PubMed  CAS  Google Scholar 

  18. Asakawa A, Inui A, Kaga T. Antagonism of ghrelin receptor reduces food intake and body weight gain in mice. Gut 2003, 52: 947–52.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  19. Murakami N, Hayashida T, Kuroiwa T. Role for central ghrelin in food intake and secretion profile of stomach ghrelin in rats. J Endocrinol 2002, 174: 283–8.

    Article  PubMed  CAS  Google Scholar 

  20. Shuto Y, Shibasaki T, Otagiri A, et al. Hypothalamic growth hormone secretagogue receptor regulates growth hormone secretion, feeding, and adiposity. J Clin Invest 2002, 109: 1429–36.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  21. Nass R, Gilrain J, Anderson S et al. High plasma growth hormone (GH) levels inhibit expression of GH secretagogue receptor messenger ribonucleic acid levels in the rat pituitary. Endocrinology 2000, 141: 2084–9.

    PubMed  CAS  Google Scholar 

  22. Kineman RD, Kamegai J, Frohman LA. Growth hormone (GH)-releasing hormone (GHRH) and the GH secretagogue (GHS), L692,585, differentially modulate rat pituitary GHS receptor and GHRH receptor messenger ribonucleic acid levels. Endocrinology 1999, 140: 3581–6.

    PubMed  CAS  Google Scholar 

  23. Kamegai J, Wakabayashi I, Miyamoto K, Unterman TG, Kineman RD, Frohman LA. Growth hormone-dependent regulation of pituitary GH secretagogue receptor (GHS-R) mRNA levels in the spontaneous dwarf Rat. Neuroendocrinology 1998, 68: 312–8.

    Article  PubMed  CAS  Google Scholar 

  24. Bennett PA, Thomas GB, Howard AD, et al. Hypothalamic growth hormone secretagogue-receptor (GHS-R) expression is regulated by growth hormone in the rat. Endocrinology 1997, 138: 4552–7.

    Article  PubMed  CAS  Google Scholar 

  25. Müller EE, Locatelli V, Cocchi D. Neuroendocrine control of growth hormone secretion. Physiol Rev 1999, 79: 511–607.

    PubMed  Google Scholar 

  26. de Gennaro Colonna V, Fidone F, Cocchi D, Müller EE. Feedback effects of growth hormone on growth hormone-releasing hormone and somatostatin are not evident in old rats. Neurobiol Aging 1993, 14: 503–7.

    Article  PubMed  Google Scholar 

  27. Veldhuis JD. Altered pulsatile and coordinate secretion of pituitary hormones in aging: evidence of feedback disruption. Aging (Milano) 1997, 9: 19–20.

    CAS  Google Scholar 

  28. Lall S, Tung LY, Ohlsson C, Jansson JO, Dickson SL. Growth hormone (GH)-independent stimulation of adiposity by GH secretagogues. Biochem Biophys Res Commun 2001, 280: 132–8.

    Article  PubMed  CAS  Google Scholar 

  29. Tschöp M, Statnick MA, Suter TM, Heiman ML. GH-releasing peptide-2 increases fat mass in mice lacking NPY: indication for a crucial mediating role of hypothalamic agouti-related protein. Endocrinology 2002, 143: 558–68.

    Article  PubMed  Google Scholar 

  30. Thompson NM, Gill DA, Davies R, 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: 234–42.

    Article  PubMed  CAS  Google Scholar 

  31. Halem HA, Taylor JE, Dong JZ, et al. A novel growth hormone secretagogue-1a receptor antagonist that blocks ghrelin-induced growth hormone secretion but induces increased body weight gain. Neuroendocrinology 2005, 81: 339–49.

    Article  PubMed  CAS  Google Scholar 

  32. Hosoda H, Kojima M, Matsuo H, Kangawa K. Ghrelin and des-acyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue. Biochem Biophys Res Commun 2000, 279: 909–13.

    Article  PubMed  CAS  Google Scholar 

  33. Bednarek MA, Feighner SD, Pong SS, et al. Structure-function studies on the new growth hormone-releasing peptide, ghrelin: minimal sequence of ghrelin necessary for activation of growth hormone secretagogue receptor 1a. J Med Chem 2000, 43: 4370–6.

    Article  PubMed  CAS  Google Scholar 

  34. Rodrigue-Way A, Demers A, Ong H, Tremblay A. A growth hormone-releasing peptide promotes mitochondrial biogenesis and a fat burning-like phenotype through scavenger receptor CD36 in white adipocytes. Endocrinology 2007, 148: 1009–18.

    Article  PubMed  CAS  Google Scholar 

  35. Avallone R, Demers A, Rodrigue-Way A, et al. A growth hormonereleasing peptide that binds scavenger receptor CD36 and ghrelin receptor up-regulates sterol transporters and cholesterol efflux in macrophages through a peroxisome proliferator-activated receptor gamma-dependent pathway. Mol Endocrinol 2006, 20: 3165–78.

    Article  PubMed  CAS  Google Scholar 

  36. Bodart V, Febbraio M, Demers A, et al. CD36 mediates the cardiovascular action of growth hormone-releasing peptides in the heart. Circ Res 2002, 90: 844–9.

    Article  PubMed  CAS  Google Scholar 

  37. Wells T Houston PA. Skeletal growth acceleration with growth hormone secretagogues in transgenic growth retarded rats: patterndependent effects and mechanisms of desensitization. J Meuroendocrinol 2001, 13: 496–504

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Experimental Medicine, University of Milano-Bicocca, via Cadore 48, 20052, Monza, Italy

    E. Bresciani PhD, L. Tamiazzo, M. Luoni, I. Bulgarelli, V. Locatelli & A. Torsello

  2. Department of Pharmacology, School of Medicine, University of Thessaly, Larissa, Greece

    N. Pitsikas

  3. Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia

    D. Cocchi

  4. Interdepartmental Center for Bioinformatics and Proteomics, University of Milano-Bicocca, Monza, Italy

    V. Locatelli & A. Torsello

Authors
  1. E. Bresciani PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N. Pitsikas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L. Tamiazzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Luoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. I. Bulgarelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D. Cocchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. V. Locatelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A. Torsello
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. Bresciani PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bresciani, E., Pitsikas, N., Tamiazzo, L. et al. Feeding behavior during long-term hexarelin administration in young and old rats. J Endocrinol Invest 31, 647–652 (2008). https://doi.org/10.1007/BF03345618

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03345618

Key-words

Search

Navigation