Table of Contents
International Journal of Peptides
Volume 2010, Article ID 864342, 7 pages
http://dx.doi.org/10.1155/2010/864342
Review Article

Metabolic and Cardiovascular Effects of Ghrelin

1Department of Medicina Interna, Università di Tor Vergata, 00133 Rome, Italy
2Istituto di Patologia Speciale Medica e Semeiotica Medica, Università Cattolica del Sacro Cuore, 00168 Roma, Italy

Received 19 November 2009; Accepted 16 January 2010

Academic Editor: Alessandro Laviano

Copyright © 2010 Manfredi Tesauro et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. M. Kojima, H. Hosoda, Y. Date, M. Nakazato, H. Matsuo, and K. Kangawa, “Ghrelin is a growth-hormone-releasing acylated peptide from stomach,” Nature, vol. 402, no. 6762, pp. 656–660, 1999. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  2. O. Gualillo, F. Lago, J. Gómez-Reino, F. F. Casanueva, and C. Dieguez, “Ghrelin, a widespread hormone: insights into molecular and cellular regulation of its expression and mechanism of action,” FEBS Letters, vol. 552, no. 2-3, pp. 105–109, 2003. View at Publisher · View at Google Scholar · View at Scopus
  3. A. J. van der Lely, M. Tschöp, M. L. Heiman, and E. Ghigo, “Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin,” Endocrine Reviews, vol. 25, no. 3, pp. 426–457, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  4. E. Ghigo, F. Broglio, E. Arvat, M. Maccario, M. Papotti, and G. Muccioli, “Ghrelin: more than a natural GH secretagogue and/or an orexigenic factor,” Clinical Endocrinology, vol. 62, no. 1, pp. 1–17, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  5. J.-M. Cao, H. Ong, and C. Chen, “Effects of ghrelin and synthetic GH secretagogues on the cardiovascular system,” Trends in Endocrinology and Metabolism, vol. 17, no. 1, pp. 13–18, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  6. M. Kojima, H. Hosoda, H. Matsuo, and K. Kangawa, “Ghrelin: discovery of the natural endogenous ligand for the growth hormone secretagogue receptor,” Trends in Endocrinology and Metabolism, vol. 12, no. 3, pp. 118–122, 2001. View at Google Scholar · View at Scopus
  7. M. P. Wajnrajch, I. S. Ten, J. M. Gertner, and R. L. Leibel, “Genomic organization of the human ghrelin gene,” Journal of Endocrine Genetics, vol. 1, no. 4, pp. 231–233, 2000. View at Google Scholar · View at Scopus
  8. J. A. Gutierrez, P. J. Solenberg, D. R. Perkins et al., “Ghrelin octanoylation mediated by an orphan lipid transferase,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 17, pp. 6320–6325, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  9. J. Yang, M. S. Brown, G. Liang, N. V. Grishin, and J. L. Goldstein, “Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone,” Cell, vol. 132, no. 3, pp. 387–396, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  10. H. Kirchner, J. A. Gutierrez, P. J. Solenberg et al., “GOAT links dietary lipids with the endocrine control of energy balance,” Nature Medicine, vol. 15, no. 7, pp. 741–745, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  11. M. A. Bednarek, S. D. Feighner, S.-S. Pong 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,” Journal of Medicinal Chemistry, vol. 43, no. 23, pp. 4370–4376, 2000. View at Publisher · View at Google Scholar · View at Scopus
  12. G. Muccioli, M. Papotti, V. Locatelli, E. Ghigo, and R. Deghenghi, “Binding of 125I-labeled ghrelin to membranes from human hypothalamus and pituitary gland,” Journal of Endocrinological Investigation, vol. 24, no. 3, pp. RC7–RC9, 2001. View at Google Scholar · View at Scopus
  13. F. Broglio, F. Prodam, E. Me et al., “Ghrelin: endocrine, metabolic and cardiovascular actions,” Journal of Endocrinological Investigation, vol. 28, no. 5, pp. 23–25, 2005. View at Google Scholar · View at Scopus
  14. M. Korbonits, A. P. Goldstone, M. Gueorguiev, and A. B. Grossman, “Ghrelin—a hormone with multiple functions,” Frontiers in Neuroendocrinology, vol. 25, no. 1, pp. 27–68, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  15. A. Asakawa, A. Inui, M. Fujimiya et al., “Stomach regulates energy balance via acylated ghrelin and desacyl ghrelin,” Gut, vol. 54, no. 1, pp. 18–24, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  16. C.-Y. Chen, A. Inui, A. Asakawa et al., “Des-acyl ghrelin acts by CRF type 2 receptors to disrupt fasted stomach motility in conscious rats,” Gastroenterology, vol. 129, no. 1, pp. 8–25, 2005. View at Publisher · View at Google Scholar · View at Scopus
  17. K. Toshinai, H. Yamaguchi, Y. Sun et al., “Des-acyl ghrelin induces food intake by a mechanism independent of the growth hormone secretagogue receptor,” Endocrinology, vol. 147, no. 5, pp. 2306–2314, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  18. H. Hosoda, M. Kojima, and K. Kangawa, “Ghrelin and the regulation of food intake and energy balance,” Molecular Interventions, vol. 2, no. 8, pp. 494–503, 2002. View at Google Scholar · View at Scopus
  19. S. M. Pöykkö, E. Kellokoski, S. Hörkkö, H. Kauma, Y. A. Kesäniemi, and O. Ukkola, “Low plasma ghrelin is associated with insulin resistance, hypertension, and the prevalence of type 2 diabetes,” Diabetes, vol. 52, no. 10, pp. 2546–2553, 2003. View at Publisher · View at Google Scholar · View at Scopus
  20. T. Shiiya, M. Nakazato, M. Mizuta et al., “Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion,” Journal of Clinical Endocrinology and Metabolism, vol. 87, no. 1, pp. 240–244, 2002. View at Publisher · View at Google Scholar · View at Scopus
  21. L. Soriano-Guillén, V. Barrios, Á. Campos-Barros, and J. Argente, “Ghrelin levels in obesity and anorexia nervosa: effect of weight reduction or recuperation,” Journal of Pediatrics, vol. 144, no. 1, pp. 36–42, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  22. D. E. Cummings, D. S. Weigle, R. S. Frayo et al., “Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery,” New England Journal of Medicine, vol. 346, no. 21, pp. 1623–1630, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  23. D. E. Cummings, K. Clement, J. Q. Purnell et al., “Elevated plasma ghrelin levels in Prader-Willi syndrome,” Nature Medicine, vol. 8, no. 7, pp. 643–644, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  24. M. Tschop, D. L. Smiley, and M. L. Heiman, “Ghrelin induces adiposity in rodents,” Nature, vol. 407, no. 6806, pp. 908–913, 2000. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  25. M. Groschl, I. Knerr, H.-G. Topf, P. Schmid, W. Rascher, and M. Rauh, “Endocrine responses to the oral ingestion of a physiological dose of essential amino acids in humans,” Journal of Endocrinology, vol. 179, no. 2, pp. 237–244, 2003. View at Publisher · View at Google Scholar · View at Scopus
  26. J. Erdmann, F. Lippl, and V. Schusdziarra, “Differential effect of protein and fat on plasma ghrelin levels in man,” Regulatory Peptides, vol. 116, no. 1–3, pp. 101–107, 2003. View at Publisher · View at Google Scholar · View at Scopus
  27. N. Nagaya, K. Miyatake, M. Uematsu et al., “Hemodynamic, renal, and hormonal effects of ghrelin infusion in patients with chronic heart failure,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 12, pp. 5854–5859, 2001. View at Publisher · View at Google Scholar · View at Scopus
  28. E. V. Dimaraki and C. A. Jaffe, “Role of endogenous ghrelin in growth hormone secretion, appetite regulation and metabolism,” Reviews in Endocrine and Metabolic Disorders, vol. 7, no. 4, pp. 237–249, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  29. M. Murata, Y. Okimura, K. Iida et al., “Ghrelin modulates the downstream molecules of insulin signaling in hepatoma cells,” Journal of Biological Chemistry, vol. 277, no. 7, pp. 5667–5674, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  30. F. Broglio, A. Benso, C. Castiglioni et al., “The endocrine response to ghrelin as a function of gender in humans in young and elderly subjects,” Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 4, pp. 1537–1542, 2003. View at Publisher · View at Google Scholar · View at Scopus
  31. M. Tschöp, C. Weyer, P. A. Tataranni, V. Devanarayan, E. Ravussin, and M. L. Heiman, “Circulating ghrelin levels are decreased in human obesity,” Diabetes, vol. 50, no. 4, pp. 707–709, 2001. View at Google Scholar · View at Scopus
  32. U. Pagotto, A. Gambineri, V. Vicennati, M. L. Heiman, M. Tschöp, and R. Pasquali, “Plasma ghrelin, obesity, and the polycystic ovary syndrome: correlation with insulin resistance and androgen levels,” Journal of Clinical Endocrinology and Metabolism, vol. 87, no. 12, pp. 5625–5629, 2002. View at Publisher · View at Google Scholar · View at Scopus
  33. B. Fagerberg, L. M. Hultén, and J. Hulthe, “Plasma ghrelin, body fat, insulin resistance, and smoking in clinically healthy men: the atherosclerosis and insulin resistance study,” Metabolism, vol. 52, no. 11, pp. 1460–1463, 2003. View at Publisher · View at Google Scholar · View at Scopus
  34. C. Langenberg, J. Bergstrom, G. A. Laughlin, and E. Barrett-Connor, “Ghrelin and the metabolic syndrome in older adults,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 12, pp. 6448–6453, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  35. S. P. Hye, K.-U. Lee, S. K. Young, and Y. P. Cheol, “Relationships between fasting plasma ghrelin levels and metabolic parameters in children and adolescents,” Metabolism, vol. 54, no. 7, pp. 925–929, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  36. D. L. Williams, H. J. Grill, D. E. Cummings, and J. M. Kaplan, “Vagotomy dissociates short- and long-term controls of circulating ghrelin,” Endocrinology, vol. 144, no. 12, pp. 5184–5187, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  37. K. Choi, S.-G. Roh, Y.-H. Hong et al., “The role of ghrelin and growth hormone secretagogues receptor on rat adipogenesis,” Endocrinology, vol. 144, no. 3, pp. 754–759, 2003. View at Publisher · View at Google Scholar · View at Scopus
  38. N. M. Thompson, D. A. S. Gill, R. Davies et al., “Ghrelin and des-octanoyl ghrelin promote adipogenesis directlyin vivo by a mechanism independent of GHS-R1a,” Endocrinology, vol. 145, no. 1, pp. 234–242, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  39. T. Tsubone, T. Masaki, I. Katsuragi, K. Tanaka, T. Kakuma, and H. Yoshimatsu, “Ghrelin regulates adiposity in white adipose tissue and UCP1 mRNA expression in brown adipose tissue in mice,” Regulatory Peptides, vol. 130, no. 1-2, pp. 97–103, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  40. S. Ghelardoni, V. Carnicelli, S. Frascarelli, S. Ronca-Testoni, and R. Zucchi, “Ghrelin tissue distribution: comparison between gene and protein expression,” Journal of Endocrinological Investigation, vol. 29, no. 2, pp. 115–121, 2006. View at Google Scholar · View at Scopus
  41. M. Korbonits, S. A. Bustin, M. Kojima et al., “The expression of the growth hormone secretagogue receptor ligand ghrelin in normal and abnormal human pituitary and other neuroendocrine tumors,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 2, pp. 881–887, 2001. View at Publisher · View at Google Scholar · View at Scopus
  42. M. Volante, E. Allìa, P. Gugliotta et al., “Expression of ghrelin and of the GH secretagogue receptor by pancreatic islet cells and related endocrine tumors,” Journal of Clinical Endocrinology and Metabolism, vol. 87, no. 3, pp. 1300–1308, 2002. View at Publisher · View at Google Scholar · View at Scopus
  43. K. K. McKee, O. C. Palyha, S. D. Feighner et al., “Molecular analysis of rat pituitary and hypothalamic growth hormone secretagogue receptors,” Molecular Endocrinology, vol. 11, no. 4, pp. 415–423, 1997. View at Publisher · View at Google Scholar · View at Scopus
  44. A. F. Leite-Moreira, A. Rocha-Sousa, and T. Henriques-Coelho, “Cardiac, skeletal, and smooth muscle regulation by ghrelin,” Vitamins and Hormones, vol. 77, pp. 207–238, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  45. M. Papotti, C. Ghè, P. Cassoni et al., “Growth hormone secretagogue binding sites in peripheral human tissues,” Journal of Clinical Endocrinology and Metabolism, vol. 85, no. 10, pp. 3803–3807, 2000. View at Google Scholar · View at Scopus
  46. S. Gnanapavan, B. Kola, S. A. Bustin et al., “The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans,” Journal of Clinical Endocrinology and Metabolism, vol. 87, no. 6, pp. 2988–2991, 2002. View at Publisher · View at Google Scholar · View at Scopus
  47. P. Cassoni, M. Papotti, C. Ghè et al., “Identification, characterization, and biological activity of specific receptors for natural (ghrelin) and synthetic growth hormone secretagogues and analogs in human breast carcinomas and cell lines,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 4, pp. 1738–1745, 2001. View at Publisher · View at Google Scholar · View at Scopus
  48. M. J. Kleinz, J. J. Maguire, J. N. Skepper, and A. P. Davenport, “Functional and immunocytochemical evidence for a role of ghrelin and des-octanoyl ghrelin in the regulation of vascular tone in man,” Cardiovascular Research, vol. 69, no. 1, pp. 227–235, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  49. S. D. Katugampola, Z. Pallikaros, and A. P. Davenport, “[125I-His9]-ghrelin, a novel radioligand for localizing GHS orphan receptors in human and rat tissue; up-regulation of receptors with atherosclerosis,” British Journal of Pharmacology, vol. 134, no. 1, pp. 143–149, 2001. View at Google Scholar · View at Scopus
  50. G. Baldanzi, N. Filigheddu, S. Cutrupi et al., “Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT,” Journal of Cell Biology, vol. 159, no. 6, pp. 1029–1037, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  51. N. Nagaya, M. Uematsu, M. Kojima et al., “Elevated circulating level of ghrelin in cachexia associated with chronic heart failure: relationships between ghrelin and anabolic/catabolic factors,” Circulation, vol. 104, no. 17, pp. 2034–2038, 2001. View at Google Scholar · View at Scopus
  52. S. Frascarelli, S. Ghelardoni, S. Ronca-Testoni, and R. Zucchi, “Effect of ghrelin and synthetic growth hormone secretagogues in normal and ischemic rat heart,” Basic Research in Cardiology, vol. 98, no. 6, pp. 401–405, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  53. N. Nagaya, M. Uematsu, M. Kojima et al., “Chronic administration of ghrelin improves left ventricular dysfunction and attenuates development of cardiac cachexia in rats with heart failure,” Circulation, vol. 104, no. 12, pp. 1430–1435, 2001. View at Google Scholar · View at Scopus
  54. N. Nagaya, M. Kojima, M. Uematsu et al., “Hemodynamic and hormonal effects of human ghrelin in healthy volunteers,” American Journal of Physiology, vol. 280, no. 5, pp. R1483–R1487, 2001. View at Google Scholar · View at Scopus
  55. N. Nagaya, J. Moriya, Y. Yasumura et al., “Effects of ghrelin administration on left ventricular function, exercise capacity, and muscle wasting in patients with chronic heart failure,” Circulation, vol. 110, no. 24, pp. 3674–3679, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  56. N. Nagaya, M. Kojima, and K. Kangawa, “Ghrelin, a novel growth hormone-releasing peptide, in the treatment of cardiopulmonary-associated cachexia,” Internal Medicine, vol. 45, no. 3, pp. 127–134, 2006. View at Publisher · View at Google Scholar · View at Scopus
  57. D. Ashby, P. Choi, and S. Bloom, “Gut hormones and the treatment of disease cachexia,” Proceedings of the Nutrition Society, vol. 67, no. 3, pp. 263–269, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  58. K. Mizia-Stec, B. Zahorska-Markiewicz, M. Olszanecka-Glinianowicz et al., “Ghrelin as a potential blood pressure reducing factor in obese women during weight loss treatment,” Endokrynologia Polska, vol. 59, no. 3, pp. 207–211, 2008. View at Google Scholar · View at Scopus
  59. T. Soeki, I. Kishimoto, D. O. Schwenke et al., “Ghrelin suppresses cardiac sympathetic activity and prevents early left ventricular remodeling in rats with myocardial infarction,” American Journal of Physiology, vol. 294, no. 1, pp. H426–H432, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  60. E. A. García and M. Korbonits, “Ghrelin and cardiovascular health,” Current Opinion in Pharmacology, vol. 6, no. 2, pp. 142–147, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  61. K. E. Wiley and A. P. Davenport, “Comparison of vasodilators in human internal mammary artery: ghrelin is a potent physiological antagonist of endothelin-1,” British Journal of Pharmacology, vol. 136, no. 8, pp. 1146–1152, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  62. M. Tesauro, F. Schinzari, M. Iantorno et al., “Ghrelin improves endothelial function in patients with metabolic syndrome,” Circulation, vol. 112, no. 19, pp. 2986–2992, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  63. M. Iantorno, H. Chen, J.-A. Kim et al., “Ghrelin has novel vascular actions that mimic PI 3-kinase-dependent actions of insulin to stimulate production of NO from endothelial cells,” American Journal of Physiology, vol. 292, no. 3, pp. E756–E764, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  64. M. Tesauro, F. Schinzari, V. Rovella et al., “Ghrelin restores the endothelin 1/nitric oxide balance in patients with obesity-related metabolic syndrome,” Hypertension, vol. 54, no. 5, pp. 995–1000, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  65. J. Pettersson, G. Muccioli, R. Granata et al., “Natural (ghrelin) and synthetic (hexarelin) GH secretagogues stimulate H9c2 cardiomyocyte cell proliferation,” Journal of Endocrinology, vol. 175, no. 1, pp. 201–209, 2002. View at Publisher · View at Google Scholar · View at Scopus
  66. M. J. Iglesias, R. Piñeiro, M. Blanco et al., “Growth hormone releasing peptide (ghrelin) is synthesized and secreted by cardiomyocytes,” Cardiovascular Research, vol. 62, no. 3, pp. 481–488, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  67. J. Isgaard, A. Barlind, and I. Johansson, “Cardiovascular effects of ghrelin and growth hormone secretagogues,” Cardiovascular and Hematological Disorders: Drug Targets, vol. 8, no. 2, pp. 133–137, 2008. View at Publisher · View at Google Scholar · View at Scopus
  68. B. Kola, E. Hubina, S. A. Tucci et al., “Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase,” Journal of Biological Chemistry, vol. 280, no. 26, pp. 25196–25201, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  69. V. D. Dixit, E. M. Schaffer, R. S. Pyle et al., “Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells,” Journal of Clinical Investigation, vol. 114, no. 1, pp. 57–66, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  70. M. Granado, T. Priego, A. I. Martín, M. Villanúa, and A. López-Calderón, “Anti-inflammatory effect of the ghrelin agonist growth hormone-releasing peptide-2 (GHRP-2) in arthritic rats,” American Journal of Physiology, vol. 288, no. 3, pp. E486–E492, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  71. M. D. DeBoer, X. Zhu, P. R. Levasseur et al., “Ghrelin treatment of chronic kidney disease: improvements in lean body mass and cytokine profile,” Endocrinology, vol. 149, no. 2, pp. 827–835, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  72. W. G. Li, D. Gavrila, X. Liu et al., “Ghrelin inhibits proinflammatory responses and nuclear factor-κB activation in human endothelial cells,” Circulation, vol. 109, no. 18, pp. 2221–2226, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus