Role of endogenous ghrelin in growth hormone secretion, appetite regulation and metabolism

Abstract

Ghrelin, a 28-amino acid hormone that is acylated post-translation, is the endogenous ligand for the growth hormone (GH) secretagogue (GHS) receptor (GHS-R). The highest concentrations of ghrelin are found in the stomach; however ghrelin peptide is also present in hypothalamic nuclei known to be important in the control of GH and feeding behavior. Exogenous ghrelin potently stimulates pituitary GH release through a mechanism that is dependent, in part, on endogenous GH-releasing hormone. Whether endogenous ghrelin plays a role in the control of GH secretion and growth is not clear and ghrelin deficient animals appear to grow normally. In contrast, experimental animal and clinical data suggest that abnormalities in GHS-R signaling could impact growth. Ghrelin or other GHS are clinically useful for GH-testing and limited data suggest that they might be useful in the treatment of some patients with GH deficiency. Substantial data have implicated ghrelin as an important regulator of feeding behavior and energy equilibrium. Ghrelin has a potent orexigenic effect in both animals and humans and this effect is mediated through hypothalamic neuropeptide Y (NPY) and Agouti-related peptide (AgRP). Appetite simulation coupled with other metabolic effects promotes weight gain during chronic treatment with ghrelin. These metabolic effects are in part mediated through an increase in respiratory quotient (VQ). Presence of ghrelin appears to be necessary for the development of obesity in some animal models. Whether abnormalities in ghrelin signaling are involved in human obesity is not yet known.

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

Fig. 1
Fig. 2

References

  1. 1.

    Bowers CY. Growth hormone-releasing peptide (GHRP). Cell Mol Life Sci 1998;54 12:1316–29.

    PubMed  CAS  Article  Google Scholar 

  2. 2.

    Smith RG, Cheng K, Schoen WR, Pong SS, Hickey G, Jacks T, et al. A nonpeptidyl growth hormone secretagogue. Science 1993;260 5114:1640–3.

    PubMed  CAS  Article  Google Scholar 

  3. 3.

    Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 1996;273 5277:974–7.

    PubMed  CAS  Article  Google Scholar 

  4. 4.

    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 6762:656–60.

    PubMed  CAS  Article  Google Scholar 

  5. 5.

    Leonetti F, Silecchia G, Iacobellis G, Ribaudo MC, Zappaterreno A, Tiberti C, et al. Different plasma ghrelin levels after laparoscopic gastric bypass and adjustable gastric banding in morbid obese subjects. J Clin Endocrinol Metab 2003;88 9:4227–31.

    PubMed  CAS  Article  Google Scholar 

  6. 6.

    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 2000;275 29:21995–2000.

    PubMed  CAS  Article  Google Scholar 

  7. 7.

    Kojima M, Kangawa K. Ghrelin: structure and function. Physiol Rev 2005;85 2:495–522.

    PubMed  CAS  Article  Google Scholar 

  8. 8.

    Beaumont NJ, Skinner VO, Tan TM, Ramesh BS, Byrne DJ, MacColl GS, et al. Ghrelin can bind to a species of high density lipoprotein associated with paraoxonase. J Biol Chem 2003;278 11:8877–80.

    PubMed  CAS  Article  Google Scholar 

  9. 9.

    Baldanzi G, Filigheddu N, Cutrupi S, Catapano F, Bonissoni S, Fubini A, et al. Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT. J Cell Biol 2002;159 6:1029–37.

    PubMed  CAS  Article  Google Scholar 

  10. 10.

    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 1:234–42.

    PubMed  CAS  Article  Google Scholar 

  11. 11.

    Carreira MC, Camina JP, Smith RG, Casanueva FF. Agonist-specific coupling of growth hormone secretagogue receptor type 1a to different intracellular signaling systems. Role of adenosine. Neuroendocrinology 2004;79 1:13–25.

    PubMed  CAS  Article  Google Scholar 

  12. 12.

    Groschl M, Uhr M, Kraus T. Evaluation of the comparability of commercial ghrelin assays. Clin Chem 2004;50 2:457–8.

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    De Vriese C, Gregoire F, Lema-Kisoka R, Waelbroeck M, Robberecht P, Delporte C. Ghrelin degradation by serum and tissue homogenates: identification of the cleavage sites. Endocrinology 2004;145 11:4997–5005.

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Arvat E, Di Vito L, Broglio F, Papotti M, Muccioli G, Dieguez C, et al. Preliminary evidence that Ghrelin, the natural GH secretagogue (GHS)-receptor ligand, strongly stimulates GH secretion in humans. J Endocrinol Investig 2000;23 8:493–5.

    CAS  Google Scholar 

  15. 15.

    Takaya K, Ariyasu H, Kanamoto N, Iwakura H, Yoshimoto A, Harada M, et al. Ghrelin strongly stimulates growth hormone release in humans. J Clin Endocrinol Metab 2000;85 12:4908–11.

    PubMed  CAS  Article  Google Scholar 

  16. 16.

    Lucidi P, Murdolo G, Di Loreto C, Parlanti N, De Cicco A, Fatone C, et al. Metabolic and endocrine effects of physiological increments in plasma ghrelin concentrations. Nutr Metab Cardiovasc Dis 2005;15 6:410–7.

    PubMed  Article  Google Scholar 

  17. 17.

    Giustina A, Veldhuis JD. Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human. Endocr Rev 1998;19 6:717–97.

    PubMed  CAS  Article  Google Scholar 

  18. 18.

    Frohman LA, Downs TR, Clarke IJ, Thomas GB. Measurement of growth hormone-releasing hormone and somatostatin in hypothalamic-portal plasma of unanesthetized sheep. Spontaneous secretion and response to insulin-induced hypoglycemia. J Clin Invest 1990;86 1:17–24.

    PubMed  CAS  Google Scholar 

  19. 19.

    Guillaume V, Magnan E, Cataldi M, Dutour A, Sauze N, Renard M, et al. Growth hormone (GH)-releasing hormone secretion is stimulated by a new GH-releasing hexapeptide in sheep. Endocrinology 1994;135 3:1073–6.

    PubMed  CAS  Article  Google Scholar 

  20. 20.

    Dimaraki EV, Jaffe CA, Bowers CY, Marbach P, Barkan AL. Pulsatile and nocturnal growth hormone secretions in men do not require periodic declines of somatostatin. Am J Physiol: Endocrinol Metab 2003;285 1:E163–70.

    CAS  Google Scholar 

  21. 21.

    Smith RG. Development of growth hormone secretagogues. Endocr Rev 2005;26 3:346–60.

    PubMed  CAS  Article  Google Scholar 

  22. 22.

    Korbonits M, Goldstone AP, Gueorguiev M, Grossman AB. Ghrelin—a hormone with multiple functions. Front Neuroendocrinol 2004;25 1:27–68.

    PubMed  CAS  Article  Google Scholar 

  23. 23.

    Cheng K, Chan WW, Barreto A, Jr., Convey, EM, Smith RG. The synergistic effects of His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 on growth hormone (GH)-releasing factor-stimulated GH release and intracellular adenosine 3′,5′-monophosphate accumulation in rat primary pituitary cell culture. Endocrinology 1989;124 6:2791–8.

    PubMed  CAS  Article  Google Scholar 

  24. 24.

    Cunha SR, Mayo KE. Ghrelin and growth hormone (GH) secretagogues potentiate GH-releasing hormone (GHRH)-induced cyclic adenosine 3′,5′-monophosphate production in cells expressing transfected GHRH and GH secretagogue receptors. Endocrinology 2002;143 12:4570–82.

    PubMed  CAS  Article  Google Scholar 

  25. 25.

    Malagon MM, Luque RM, Ruiz-Guerrero E, Rodriguez-Pacheco F, Garcia-Navarro S, Casanueva FF, et al. Intracellular signaling mechanisms mediating ghrelin-stimulated growth hormone release in somatotropes. Endocrinology 2003;144 12:5372–80.

    PubMed  CAS  Article  Google Scholar 

  26. 26.

    Sato T, Fukue Y, Teranishi H, Yoshida Y, Kojima M. Molecular forms of hypothalamic ghrelin and its regulation by fasting and 2-deoxy-d-glucose administration. Endocrinology 2005;146 6:2510–6.

    PubMed  CAS  Article  Google Scholar 

  27. 27.

    Kamegai J, Tamura H, Shimizu T, Ishii S, Tatsuguchi A, Sugihara H, et al. The role of pituitary ghrelin in growth hormone (GH) secretion: GH-releasing hormone-dependent regulation of pituitary ghrelin gene expression and peptide content. Endocrinology 2004;145 8:3731–8.

    PubMed  CAS  Article  Google Scholar 

  28. 28.

    Bowers CY. Unnatural growth hormone-releasing peptide begets natural ghrelin. J Clin Endocrinol Metab 2001;86 4:1464–9.

    PubMed  CAS  Article  Google Scholar 

  29. 29.

    Hickey GJ, Drisko J, Faidley T, Chang C, Anderson LL, Nicolich S, et al. Mediation by the central nervous system is critical to the in vivo activity of the GH secretagogue L-692,585. J Endocrinol 1996;148 2:371–80.

    PubMed  CAS  Article  Google Scholar 

  30. 30.

    Popovic V, Damjanovic S, Micic D, Djurovic M, Dieguez C, Casanueva FF. Blocked growth hormone-releasing peptide (GHRP-6)-induced GH secretion and absence of the synergic action of GHRP-6 plus GH-releasing hormone in patients with hypothalamopituitary disconnection: evidence that GHRP-6 main action is exerted at the hypothalamic level. J Clin Endocrinol Metab 1995;80 3:942–7.

    PubMed  CAS  Article  Google Scholar 

  31. 31.

    Tannenbaum GS, Lapointe M, Beaudet A, Howard AD. Expression of growth hormone secretagogue-receptors by growth hormone-releasing hormone neurons in the mediobasal hypothalamus. Endocrinology 1998;139 10:4420–3.

    PubMed  CAS  Article  Google Scholar 

  32. 32.

    Dickson SL, Luckman SM. Induction of c-fos messenger ribonucleic acid in neuropeptide Y and growth hormone (GH)-releasing factor neurons in the rat arcuate nucleus following systemic injection of the GH secretagogue, GH-releasing peptide-6. Endocrinology 1997;138 2:771–7.

    PubMed  CAS  Article  Google Scholar 

  33. 33.

    Hewson AK, Dickson SL. Systemic administration of ghrelin induces Fos and Egr-1 proteins in the hypothalamic arcuate nucleus of fasted and fed rats. J Neuroendocrinol 2000;12 11:1047–9.

    PubMed  CAS  Article  Google Scholar 

  34. 34.

    Dickson SL, Leng G, Dyball RE, Smith RG. Central actions of peptide and non-peptide growth hormone secretagogues in the rat. Neuroendocrinology 1995;61 1:36–43.

    PubMed  CAS  Google Scholar 

  35. 35.

    Hewson AK, Viltart O, McKenzie DN, Dyball RE, Dickson SL. GHRP-6-induced changes in electrical activity of single cells in the arcuate, ventromedial and periventricular nucleus neurones [correction of nuclei] of a hypothalamic slice preparation in vitro. J Neuroendocrinol 1999;11 12:919–23.

    PubMed  CAS  Article  Google Scholar 

  36. 36.

    Clark RG, Carlsson LMS, Trojnar J, Robinson IC. The effects of a growth hormone-releasing peptide and growth hormone-releasing factor in conscious and anaesthetized rats. J Neuroendocrinol 1989;1 4:249–255.

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Pandya N, DeMott-Friberg R, Bowers CY, Barkan AL, Jaffe CA. Growth hormone (GH)-releasing peptide-6 requires endogenous hypothalamic GH-releasing hormone for maximal GH stimulation. J Clin Endocrinol Metab 1998;83 4:1186–9.

    PubMed  CAS  Article  Google Scholar 

  38. 38.

    Maheshwari HG, Rahim A, Shalet SM, Baumann G. Selective lack of growth hormone (GH) response to the GH-releasing peptide hexarelin in patients with GH-releasing hormone receptor deficiency. J Clin Endocrinol Metab 1999;84 3:956–9.

    PubMed  CAS  Article  Google Scholar 

  39. 39.

    Gondo RG, Aguiar-Oliveira MH, Hayashida CY, Toledo SP, Abelin N, Levine MA, et al. Growth hormone-releasing peptide-2 stimulates GH secretion in GH-deficient patients with mutated GH-releasing hormone receptor. J Clin Endocrinol Metab 2001;86 7:3279–83.

    PubMed  CAS  Article  Google Scholar 

  40. 40.

    Jansson JO, Downs TR, Beamer WG, Frohman LA. Receptor-associated resistance to growth hormone-releasing factor in “dwarf little” mice. Science 1986;232 4749:511–2.

    PubMed  CAS  Article  Google Scholar 

  41. 41.

    Fintini D, Alba M, Schally AV, Bowers CY, Parlow AF, Salvatori R. Effects of combined long-term treatment with a growth hormone-releasing hormone analogue and a growth hormone secretagogue in the growth hormone-releasing hormone knock out mouse. Neuroendocrinology 2005;82 3–4:198–207.

    PubMed  CAS  Article  Google Scholar 

  42. 42.

    Fletcher TP, Thomas GB, Clarke IJ. Growth hormone-releasing hormone and somatostatin concentrations in the hypophysial portal blood of conscious sheep during the infusion of growth hormone-releasing peptide-6. Domest Anim Endocrinol 1996;13 3:251–8.

    PubMed  CAS  Article  Google Scholar 

  43. 43.

    Drisko JE, Faidley TD, Zhang D, McDonald TJ, Nicolich S, Hora DF, et al. Administration of a nonpeptidyl growth hormone secretagogue, L-163, 255, changes somatostatin pattern, but has no effect on patterns of growth hormone-releasing factor in the hypophyseal-portal circulation of the conscious pig. Proc Soc Exp Biol Med 1999;222 1:70–7.

    PubMed  CAS  Article  Google Scholar 

  44. 44.

    Muller AF, Lamberts SW, Janssen JA, Hofland LJ, Koetsveld PV, Bidlingmaier M, et al. Ghrelin drives GH secretion during fasting in man. Eur J Endocrinol 2002;146 2:203–7.

    PubMed  CAS  Article  Google Scholar 

  45. 45.

    Avram AM, Jaffe CA, Symons KV, Barkan AL. Endogenous circulating ghrelin does not mediate growth hormone rhythmicity or response to fasting. J Clin Endocrinol Metab 2005;90 5:2982–7.

    PubMed  CAS  Article  Google Scholar 

  46. 46.

    Natalucci G, Riedl S, Gleiss A, Zidek T, Frisch H. Spontaneous 24-h ghrelin secretion pattern in fasting subjects: maintenance of a meal-related pattern. Eur J Endocrinol 2005;152 6:845–50.

    PubMed  CAS  Article  Google Scholar 

  47. 47.

    Koutkia P, Canavan B, Breu J, Johnson ML, Grinspoon SK. Nocturnal ghrelin pulsatility and response to growth hormone secretagogues in healthy men. Am J Physiol: Endocrinol Metab 2004;287 3:E506–12.

    CAS  Article  Google Scholar 

  48. 48.

    Jaffe CA, DeMott-Friberg R, Barkan AL. Endogenous growth hormone (GH)-releasing hormone is required for GH responses to pharmacological stimuli. J Clin Invest 1996;97 4:934–40.

    PubMed  CAS  Google Scholar 

  49. 49.

    Lucidi P, Murdolo G, Di Loreto C, De Cicco A, Parlanti N, Fanelli C, et al. Ghrelin is not necessary for adequate hormonal counterregulation of insulin-induced hypoglycemia. Diabetes 2002;51 10:2911–4.

    PubMed  CAS  Article  Google Scholar 

  50. 50.

    Broglio F, Gottero C, Prodam F, Destefanis S, Gauna C, Me E, et al. Ghrelin secretion is inhibited by glucose load and insulin-induced hypoglycaemia but unaffected by glucagon and arginine in humans. Clin Endocrinol (Oxf) 2004;61 4:503–9.

    CAS  Article  Google Scholar 

  51. 51.

    Matsuoka H, Hosoda H, Sugawara H, Iwama S, Kim HS, Kangawa K, et al. Short-term secretory regulation of ghrelin during growth hormone provocative tests in prepubertal children with various growth hormone secretory capacities. Horm Res 2005;64 6:274–9.

    PubMed  CAS  Article  Google Scholar 

  52. 52.

    Broglio F, Gottero C, Van Koetsveld P, Prodam F, Destefanis S, Benso A, et al. Acetylcholine regulates ghrelin secretion in humans. J Clin Endocrinol Metab 2004;89 5:2429–33.

    PubMed  CAS  Article  Google Scholar 

  53. 53.

    Maier C, Schaller G, Buranyi B, Nowotny P, Geyer G, Wolzt M, et al. The cholinergic system controls ghrelin release and ghrelin-induced growth hormone release in humans. J Clin Endocrinol Metab 2004;89 9:4729–33.

    PubMed  CAS  Article  Google Scholar 

  54. 54.

    Dall R, Kanaley J, Hansen TK, Moller N, Christiansen JS, Hosoda H, et al. Plasma ghrelin levels during exercise in healthy subjects and in growth hormone-deficient patients. Eur J Endocrinol 2002;147 1:65–70.

    PubMed  CAS  Article  Google Scholar 

  55. 55.

    Jorgensen JO, Krag M, Kanaley J, Moller J, Hansen TK, Moller N, et al. Exercise, hormones, and body temperature. Regulation and action of GH during exercise. J Endocrinol Investig 2003;26 9:838–42.

    CAS  Google Scholar 

  56. 56.

    Hataya Y, Akamizu T, Takaya K, Kanamoto N, Ariyasu H, Saijo M, et al. A low dose of ghrelin stimulates growth hormone (GH) release synergistically with GH-releasing hormone in humans. J Clin Endocrinol Metab 2001;86 9:4552.

    PubMed  CAS  Article  Google Scholar 

  57. 57.

    Katakami H, Matsukura S. Role of endogenous ghrelin in pulsatile GH secretion in conscious rats. Clin Pediatr Endocrinol 2002;11 Suppl 17:107–115.

    Google Scholar 

  58. 58.

    Zizzari P, Halem H, Taylor J, Dong JZ, Datta R, Culler MD, et al. Endogenous ghrelin regulates episodic growth hormone (GH) secretion by amplifying GH Pulse amplitude: evidence from antagonism of the GH secretagogue-R1a receptor. Endocrinology 2005;146 9:3836–42.

    PubMed  CAS  Article  Google Scholar 

  59. 59.

    Sun Y, Ahmed S, Smith RG. Deletion of ghrelin impairs neither growth nor appetite. Mol Cell Biol 2003;23 22:7973–81.

    PubMed  CAS  Article  Google Scholar 

  60. 60.

    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 2004;101 21:8227–32.

    PubMed  CAS  Article  Google Scholar 

  61. 61.

    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 2004;101 13:4679–84.

    PubMed  CAS  Article  Google Scholar 

  62. 62.

    Shuto Y, Shibasaki T, Otagiri A, Kuriyama H, Ohata H, Tamura H, et al. Hypothalamic growth hormone secretagogue receptor regulates growth hormone secretion, feeding, and adiposity. J Clin Invest 2002;109 11:1429–36.

    PubMed  CAS  Article  Google Scholar 

  63. 63.

    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 3:760–8.

    PubMed  CAS  Article  Google Scholar 

  64. 64.

    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 11:2201–10.

    PubMed  CAS  Article  Google Scholar 

  65. 65.

    Laron Z, Frenkel J, Deghenghi R, Anin S, Klinger B, Silbergeld A. Intranasal administration of the GHRP hexarelin accelerates growth in short children. Clin Endocrinol (Oxf) 1995;43 5:631–5.

    CAS  Google Scholar 

  66. 66.

    Pihoker C, Badger TM, Reynolds GA, Bowers CY. Treatment effects of intranasal growth hormone releasing peptide-2 in children with short stature. J Endocrinol 1997;155 1:79–86.

    PubMed  CAS  Article  Google Scholar 

  67. 67.

    Mericq V, Cassorla F, Salazar T, Avila A, Iniguez G, Bowers CY, et al. Effects of eight months treatment with graded doses of a growth hormone (GH)-releasing peptide in GH-deficient children. J Clin Endocrinol Metab 1998;83 7:2355–60.

    PubMed  CAS  Article  Google Scholar 

  68. 68.

    Murphy MG, Weiss S, McClung M, Schnitzer T, Cerchio K, Connor J, et al. Effect of alendronate and MK-677 (a growth hormone secretagogue), individually and in combination, on markers of bone turnover and bone mineral density in postmenopausal osteoporotic women. J Clin Endocrinol Metab 2001;86 3:1116–25.

    PubMed  CAS  Article  Google Scholar 

  69. 69.

    Bach MA, Rockwood K, Zetterberg C, Thamsborg G, Hebert R, Devogelaer JP, et al. The effects of MK-0677, an oral growth hormone secretagogue, in patients with hip fracture. J Am Geriatr Soc 2004;52 4:516–23.

    PubMed  Article  Google Scholar 

  70. 70.

    Nagaya N, Moriya J, Yasumura Y, Uematsu M, Ono F, Shimizu W, et al. Effects of ghrelin administration on left ventricular function, exercise capacity, and muscle wasting in patients with chronic heart failure. Circulation 2004;110 24:3674–9.

    PubMed  CAS  Article  Google Scholar 

  71. 71.

    Neary NM, Small CJ, Wren AM, Lee JL, Druce MR, Palmieri C, et al. Ghrelin increases energy intake in cancer patients with impaired appetite: acute, randomized, placebo-controlled trial. J Clin Endocrinol Metab 2004;89 6:2832–6.

    PubMed  CAS  Article  Google Scholar 

  72. 72.

    Nagaya N, Itoh T, Murakami S, Oya H, Uematsu M, Miyatake K, et al. Treatment of cachexia with ghrelin in patients with COPD. Chest 2005;128 3:1187–93.

    PubMed  CAS  Article  Google Scholar 

  73. 73.

    Wynne K, Giannitsopoulou K, Small CJ, Patterson M, Frost G, Ghatei MA, et al. Subcutaneous ghrelin enhances acute food intake in malnourished patients who receive maintenance peritoneal dialysis: a randomized, placebo-controlled trial. J Am Soc Nephrol 2005;16 7:2111–8.

    PubMed  CAS  Article  Google Scholar 

  74. 74.

    Abs R. Update on the diagnosis of GH deficiency in adults. Eur J Endocrinol 2003;148 Suppl 2:S3–8.

    PubMed  CAS  Article  Google Scholar 

  75. 75.

    Iqbal J, Kurose Y, Canny B, Clarke IJ. Effects of central infusion of ghrelin on food intake and plasma levels of growth hormone, luteinizing hormone, prolactin, and cortisol secretion in sheep. Endocrinology 2006;147 1:510–9.

    PubMed  CAS  Article  Google Scholar 

  76. 76.

    Tolle V, Bassant MH, Zizzari P, Poindessous-Jazat F, Tomasetto C, Epelbaum J, et al. Ultradian rhythmicity of ghrelin secretion in relation with GH, feeding behavior, and sleep-wake patterns in rats. Endocrinology 2002;143 4:1353–61.

    PubMed  CAS  Article  Google Scholar 

  77. 77.

    Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, et al. A role for ghrelin in the central regulation of feeding. Nature 2001;409 6817:194–8.

    PubMed  CAS  Article  Google Scholar 

  78. 78.

    Shintani M, Ogawa Y, Ebihara K, Aizawa-Abe M, Miyanaga F, Takaya K, et al. Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway. Diabetes 2001;50 2:227–32.

    PubMed  CAS  Article  Google Scholar 

  79. 79.

    Wren AM, Small CJ, Ward HL, Murphy KG, Dakin CL, Taheri S, et al. The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology 2000;141 11:4325–8.

    PubMed  CAS  Article  Google Scholar 

  80. 80.

    Wren AM, Small CJ, Abbott CR, Dhillo WS, Seal LJ, Cohen MA, et al. Ghrelin causes hyperphagia and obesity in rats. Diabetes 2001;50 11:2540–7.

    PubMed  CAS  Article  Google Scholar 

  81. 81.

    Asakawa A, Inui A, Kaga T, Katsuura G, Fujimiya M, Fujino MA, et al. Antagonism of ghrelin receptor reduces food intake and body weight gain in mice. Gut 2003;52 7:947–52.

    PubMed  CAS  Article  Google Scholar 

  82. 82.

    Shearman LP, Wang SP, Helmling S, Stribling DS, Mazur P, Ge L, et al. Ghrelin neutralization by a ribonucleic acid-SPM ameliorates obesity in diet-induced obese mice. Endocrinology 2006;147 3:1517–26.

    PubMed  CAS  Article  Google Scholar 

  83. 83.

    Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, et al. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 2001;86 12:5992.

    PubMed  CAS  Article  Google Scholar 

  84. 84.

    Druce MR, Wren AM, Park AJ, Milton JE, Patterson M, Frost G, et al. Ghrelin increases food intake in obese as well as lean subjects. Int J Obes (Lond) 2005;29 9:1130–6.

    CAS  Article  Google Scholar 

  85. 85.

    Druce MR, Neary NM, Small CJ, Milton J, Monteiro M, Patterson M, et al. Subcutaneous administration of ghrelin stimulates energy intake in healthy lean human volunteers. Int J Obes (Lond) 2006;30 2:293–6.

    CAS  Article  Google Scholar 

  86. 86.

    Laferrere B, Abraham C, Russell CD, Bowers CY. Growth hormone releasing peptide-2 (GHRP-2), like ghrelin, increases food intake in healthy men. J Clin Endocrinol Metab 2005;90 2:611–4.

    PubMed  CAS  Article  Google Scholar 

  87. 87.

    Guan XM, Yu H, Palyha OC, McKee KK, Feighner SD, Sirinathsinghji DJ, et al. Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Brain Res, Mol Brain Res1997;48 1:23–9.

    CAS  Article  Google Scholar 

  88. 88.

    Willesen MG, Kristensen P, Romer J. Co-localization of growth hormone secretagogue receptor and NPY mRNA in the arcuate nucleus of the rat. Neuroendocrinology 1999;70 5:306–16.

    PubMed  CAS  Article  Google Scholar 

  89. 89.

    Kamegai J, Tamura H, Shimizu T, Ishii S, Sugihara H, Wakabayashi I. Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and Agouti-related protein mRNA levels and body weight in rats. Diabetes 2001;50 11:2438–43.

    PubMed  CAS  Article  Google Scholar 

  90. 90.

    Guan JL, Wang QP, Kageyama H, Takenoya F, Kita T, Matsuoka T, et al. Synaptic interactions between ghrelin- and neuropeptide Y-containing neurons in the rat arcuate nucleus. Peptides 2003;24 12:1921–8.

    PubMed  CAS  Article  Google Scholar 

  91. 91.

    Melis MR, Mascia MS, Succu S, Torsello A, Muller EE, Deghenghi R, et al. Ghrelin injected into the paraventricular nucleus of the hypothalamus of male rats induces feeding but not penile erection. Neurosci Lett 2002;329 3:339–43.

    PubMed  CAS  Article  Google Scholar 

  92. 92.

    Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I, et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 1997;278 5335:135–8.

    PubMed  CAS  Article  Google Scholar 

  93. 93.

    Chen HY, Trumbauer ME, Chen AS, Weingarth DT, Adams JR, Frazier EG, et al. Orexigenic action of peripheral ghrelin is mediated by neuropeptide Y and agouti-related protein. Endocrinology 2004;145 6:2607–12.

    PubMed  CAS  Article  Google Scholar 

  94. 94.

    Tschop 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 2:558–68.

    PubMed  CAS  Article  Google Scholar 

  95. 95.

    Cowley MA, Smart JL, Rubinstein M, Cerdan MG, Diano S, Horvath TL, et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 2001;411 6836:480–4.

    PubMed  CAS  Article  Google Scholar 

  96. 96.

    Rodgers RJ, Ishii Y, Halford JC, Blundell JE. Orexins and appetite regulation. Neuropeptides 2002;36 5:303–25.

    PubMed  CAS  Article  Google Scholar 

  97. 97.

    Lawrence CB, Snape AC, Baudoin FM, Luckman SM. Acute central ghrelin and GH secretagogues induce feeding and activate brain appetite centers. Endocrinology 2002;143 1:155–62.

    PubMed  CAS  Article  Google Scholar 

  98. 98.

    Toshinai K, Date Y, Murakami N, Shimada M, Mondal MS, Shimbara T, et al. Ghrelin-induced food intake is mediated via the orexin pathway. Endocrinology 2003;144 4:1506–12.

    PubMed  Article  CAS  Google Scholar 

  99. 99.

    Niimi M, Sato M, Taminato T. Neuropeptide Y in central control of feeding and interactions with orexin and leptin. Endocrine 2001;14 2:269–73.

    PubMed  CAS  Article  Google Scholar 

  100. 100.

    Muroya S, Funahashi H, Yamanaka A, Kohno D, Uramura K, Nambu T, et al. Orexins (hypocretins) directly interact with neuropeptide Y, POMC and glucose-responsive neurons to regulate Ca 2+ signaling in a reciprocal manner to leptin: orexigenic neuronal pathways in the mediobasal hypothalamus. Eur J Neurosci 2004;19 6:1524–34.

    PubMed  Article  Google Scholar 

  101. 101.

    Toshinai K, Yamaguchi H, Sun Y, Smith RG, Yamanaka A, Sakurai T, et al. Des-acyl ghrelin induces food intake by a mechanism independent of the growth hormone secretagogue receptor. Endocrinology 2006;147 5:2306–14.

    PubMed  CAS  Article  Google Scholar 

  102. 102.

    Egecioglu E, Bjursell M, Ljungberg A, Dickson SL, Kopchick JJ, Bergstrom G, et al. Growth hormone receptor deficiency results in blunted ghrelin feeding response, obesity, and hypolipidemia in mice. Am J Physiol: Endocrinol Metab 2006;290 2:E317–25.

    CAS  Article  Google Scholar 

  103. 103.

    Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature 2000;407 6806:908–13.

    PubMed  CAS  Article  Google Scholar 

  104. 104.

    Currie PJ, Mirza A, Fuld R, Park D, Vasselli JR. Ghrelin is an orexigenic and metabolic signaling peptide in the arcuate and paraventricular nuclei. Am J Physiol, Regul Integr Comp Physiol 2005;289 2:R353–R358.

    CAS  Google Scholar 

  105. 105.

    Theander-Carrillo C, Wiedmer P, Cettour-Rose P, Nogueiras R, Perez-Tilve D, Pfluger P, et al. Ghrelin action in the brain controls adipocyte metabolism. J Clin Invest 2006;116 7:1983–93.

    PubMed  CAS  Article  Google Scholar 

  106. 106.

    Tang-Christensen M, Vrang N, Ortmann S, Bidlingmaier M, Horvath TL, Tschop M. Central administration of ghrelin and agouti-related protein (83–132) increases food intake and decreases spontaneous locomotor activity in rats. Endocrinology 2004;145 10:4645–52.

    PubMed  CAS  Article  Google Scholar 

  107. 107.

    Shimbara T, Mondal MS, Kawagoe T, Toshinai K, Koda S, Yamaguchi H, et al. Central administration of ghrelin preferentially enhances fat ingestion. Neurosci Lett 2004;369 1:75–9.

    PubMed  CAS  Article  Google Scholar 

  108. 108.

    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 12:3573–8.

    PubMed  CAS  Article  Google Scholar 

  109. 109.

    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 12:3564–72.

    PubMed  CAS  Article  Google Scholar 

  110. 110.

    Zigman JM, Elmquist JK. Minireview: from anorexia to obesity—the yin and yang of body weight control. Endocrinology 2003;144 9:3749–56.

    PubMed  CAS  Article  Google Scholar 

  111. 111.

    Stephens TW, Basinski M, Bristow PK, Bue-Valleskey JM, Burgett SG, Craft L, et al. The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature 1995;377 6549:530–2.

    PubMed  CAS  Article  Google Scholar 

  112. 112.

    Schwartz MW, Baskin DG, Bukowski TR, Kuijper JL, Foster D, Lasser G, et al. Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice. Diabetes 1996;45 4:531–5.

    PubMed  CAS  Article  Google Scholar 

  113. 113.

    Kim MS, Namkoong C, Kim HS, Jang PG, Kim Pak YM, Katakami H, et al. Chronic central administration of ghrelin reverses the effects of leptin. Int J Obes Related Metab Disord 2004;28 10:1264–71.

    CAS  Article  Google Scholar 

  114. 114.

    Sun Y, Asnicar M, Saha PK, Chan L, Smith RG. Ablation of ghrelin improves the diabetic but not obese phenotype of ob/ob mice. Cell Metab 2006;3 5:379–86.

    PubMed  CAS  Article  Google Scholar 

  115. 115.

    Tschop M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E, Heiman ML. Circulating ghrelin levels are decreased in human obesity. Diabetes 2001;50 4:707–9.

    PubMed  CAS  Article  Google Scholar 

  116. 116.

    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 10:4753–8.

    PubMed  CAS  Article  Google Scholar 

  117. 117.

    Shiiya T, Nakazato M, Mizuta M, Date Y, Mondal MS, Tanaka M, et al. Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion. J Clin Endocrinol Metab 2002;87 1:240–4.

    PubMed  CAS  Article  Google Scholar 

  118. 118.

    Tolle V, Kadem M, Bluet-Pajot MT, Frere D, Foulon C, Bossu C, et al. Balance in ghrelin and leptin plasma levels in anorexia nervosa patients and constitutionally thin women. J Clin Endocrinol Metab 2003;88 1:109–16.

    PubMed  CAS  Article  Google Scholar 

  119. 119.

    Leidy HJ, Gardner JK, Frye BR, Snook ML, Schuchert MK, Richard EL, et al. Circulating ghrelin is sensitive to changes in body weight during a diet and exercise program in normal-weight young women. J Clin Endocrinol Metab 2004;89 6:2659–64.

    PubMed  CAS  Article  Google Scholar 

  120. 120.

    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 8:1714–9.

    PubMed  CAS  Article  Google Scholar 

  121. 121.

    Purnell JQ, Weigle DS, Breen P, Cummings DE. Ghrelin levels correlate with insulin levels, insulin resistance, and high-density lipoprotein cholesterol, but not with gender, menopausal status, or cortisol levels in humans. J Clin Endocrinol Metab 2003;88 12:5747–52.

    PubMed  CAS  Article  Google Scholar 

  122. 122.

    McLaughlin T, Abbasi F, Lamendola C, Frayo RS, Cummings DE. Plasma ghrelin concentrations are decreased in insulin-resistant obese adults relative to equally obese insulin-sensitive controls. J Clin Endocrinol Metab 2004;89 4:1630–5.

    PubMed  CAS  Article  Google Scholar 

  123. 123.

    Katsuki A, Urakawa H, Gabazza EC, Murashima S, Nakatani K, Togashi K, et al. Circulating levels of active ghrelin is associated with abdominal adiposity, hyperinsulinemia and insulin resistance in patients with type 2 diabetes mellitus. Eur J Endocrinol 2004;151 5:573–7.

    PubMed  CAS  Article  Google Scholar 

  124. 124.

    Libe R, Morpurgo PS, Cappiello V, Maffini A, Bondioni S, Locatelli M, et al. Ghrelin and adiponectin in patients with Cushing’s disease before and after successful transsphenoidal surgery. Clin Endocrinol (Oxf) 2005;62 1:30–6.

    CAS  Article  Google Scholar 

  125. 125.

    Pagotto U, Gambineri A, Vicennati V, Heiman ML, Tschop M, Pasquali R. Plasma ghrelin, obesity, and the polycystic ovary syndrome: correlation with insulin resistance and androgen levels. J Clin Endocrinol Metab 2002;87 12:5625–9.

    PubMed  CAS  Article  Google Scholar 

  126. 126.

    Schofl C, Horn R, Schill T, Schlosser HW, Muller MJ, Brabant G. Circulating ghrelin levels in patients with polycystic ovary syndrome. J Clin Endocrinol Metab 2002;87 10:4607–10.

    PubMed  CAS  Article  Google Scholar 

  127. 127.

    Misra M, Miller KK, Kuo K, Griffin K, Stewart V, Hunter E, et al. Secretory dynamics of ghrelin in adolescent girls with anorexia nervosa and healthy adolescents. Am J Physiol: Endocrinol Metab 2005;289 2:E347–56.

    CAS  Article  Google Scholar 

  128. 128.

    Koutkia P, Schurgin S, Berry J, Breu J, Lee BS, Klibanski A, et al. Reciprocal changes in endogenous ghrelin and growth hormone during fasting in healthy women. Am J Physiol: Endocrinol Metab 2005;289 5:E814–22.

    CAS  Article  Google Scholar 

  129. 129.

    Tsai W, Ermolenko M, Jaffe CA. Feeding suppresses serum shrelin in humans. (2001) Proceedings of the 93rd Annual Meeting of the Endocrine Society, Denver, CO.

  130. 130.

    Gottero C, Bellone S, Rapa A, van Koetsveld P, Vivenza D, Prodam F, et al. Standard light breakfast inhibits circulating ghrelin level to the same extent of oral glucose load in humans, despite different impact on glucose and insulin levels. J Endocrinol Investig 2003;26 12:1203–7.

    CAS  Google Scholar 

  131. 131.

    Callahan HS, Cummings DE, Pepe MS, Breen PA, Matthys CC, Weigle DS. Postprandial suppression of plasma ghrelin level is proportional to ingested caloric load but does not predict intermeal interval in humans. J Clin Endocrinol Metab 2004;89 3:1319–24.

    PubMed  CAS  Article  Google Scholar 

  132. 132.

    Erdmann J, Topsch R, Lippl F, Gussmann P, Schusdziarra V. Postprandial response of plasma ghrelin levels to various test meals in relation to food intake, plasma insulin, and glucose. J Clin Endocrinol Metab 2004;89 6:3048–54.

    PubMed  CAS  Article  Google Scholar 

  133. 133.

    Erdmann J, Lippl F, Schusdziarra V. Differential effect of protein and fat on plasma ghrelin levels in man. Regulatory Pept 2003;116 1–3:101–7.

    CAS  Article  Google Scholar 

  134. 134.

    Barkan AL, Dimaraki EV, Jessup SK, Symons KV, Ermolenko M, Jaffe CA. Ghrelin secretion in humans is sexually dimorphic, suppressed by somatostatin, and not affected by the ambient growth hormone levels. J Clin Endocrinol Metab 2003;88 5:2180–4.

    PubMed  CAS  Article  Google Scholar 

  135. 135.

    Yildiz BO, Suchard MA, Wong ML, McCann SM, Licinio J. Alterations in the dynamics of circulating ghrelin, adiponectin, and leptin in human obesity. Proc Natl Acad Sci 2004;101 28:10434–9.

    PubMed  CAS  Article  Google Scholar 

  136. 136.

    Liu J, Prudom C, Veldhuis P, Nass R, Geysen HM, Johnson ML, et al. Rapid and profound changes in active plasma ghrelin are observed using a specific two-site sandwich ELISA and 10 min blood sampling. (2006) The Endocrine Society’s 88th Annual Meeting, Boston, MA, OR45–5.

  137. 137.

    Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 2002;346 21:1623–30.

    PubMed  Article  Google Scholar 

  138. 138.

    Cummings DE, Frayo RS, Marmonier C, Aubert R, Chapelot D. Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily without time- and food-related cues. Am J Physiol: Endocrinol Metab 2004;287 2:E297–304.

    CAS  Article  Google Scholar 

  139. 139.

    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 7:643–4.

    PubMed  CAS  Article  Google Scholar 

  140. 140.

    DelParigi A, Tschop 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 12:5461–4.

    PubMed  CAS  Article  Google Scholar 

  141. 141.

    Corbetta S, Peracchi M, Cappiello V, Lania A, Lauri E, Vago L, et al. Circulating ghrelin levels in patients with pancreatic and gastrointestinal neuroendocrine tumors: identification of one pancreatic ghrelinoma. J Clin Endocrinol Metab 2003;88 7:3117–20.

    PubMed  CAS  Article  Google Scholar 

  142. 142.

    Tsolakis AV, Portela-Gomes GM, Stridsberg M, Grimelius L, Sundin A, Eriksson BK, et al. Malignant gastric ghrelinoma with hyperghrelinemia. J Clin Endocrinol Metab 2004;89 8:3739–44.

    PubMed  CAS  Article  Google Scholar 

  143. 143.

    Salbe AD, Tschop MH, DelParigi A, Venti CA, Tataranni PA. Negative relationship between fasting plasma ghrelin concentrations and ad libitum food intake. J Clin Endocrinol Metab 2004;89 6:2951–6.

    PubMed  CAS  Article  Google Scholar 

  144. 144.

    Morinigo R, Casamitjana R, Moize V, Lacy AM, Delgado S, Gomis R, et al. Short-term effects of gastric bypass surgery on circulating ghrelin levels. Obes Res 2004;12 7:1108–16.

    PubMed  Article  Google Scholar 

  145. 145.

    Stylopoulos N, Davis P, Pettit JD, Rattner DW, Kaplan LM. Changes in serum ghrelin predict weight loss after Roux-en-Y gastric bypass in rats. Surg Endosc 2005;19 7:942–6.

    PubMed  CAS  Article  Google Scholar 

  146. 146.

    Faraj M, Havel PJ, Phelis S, Blank D, Sniderman AD, Cianflone K. Plasma acylation-stimulating protein, adiponectin, leptin, and ghrelin before and after weight loss induced by gastric bypass surgery in morbidly obese subjects. J Clin Endocrinol Metab 2003;88 4:1594–602.

    PubMed  CAS  Article  Google Scholar 

  147. 147.

    Holdstock C, Engstrom BE, Ohrvall M, Lind L, Sundbom M, Karlsson FA. Ghrelin and adipose tissue regulatory peptides: effect of gastric bypass surgery in obese humans. J Clin Endocrinol Metab 2003;88 7:3177–83.

    PubMed  CAS  Article  Google Scholar 

  148. 148.

    Hanusch-Enserer U, Cauza E, Brabant G, Dunky A, Rosen H, Pacini G, et al. Plasma ghrelin in obesity before and after weight loss after laparoscopical adjustable gastric banding. J Clin Endocrinol Metab 2004;89 7:3352–8.

    PubMed  CAS  Article  Google Scholar 

  149. 149.

    Korner J, Bessler M, Cirilo LJ, Conwell IM, Daud A, Restuccia NL, et al. Effects of Roux-en-Y gastric bypass surgery on fasting and postprandial concentrations of plasma ghrelin, peptide YY, and insulin. J Clin Endocrinol Metab 2005;90 1:359–65.

    PubMed  CAS  Article  Google Scholar 

  150. 150.

    Borg CM, le Roux CW, Ghatei MA, Bloom SR, Patel AG, Aylwin SJ. Progressive rise in gut hormone levels after Roux-en-Y gastric bypass suggests gut adaptation and explains altered satiety. Br J Surg 2006;93 2:210–5.

    PubMed  CAS  Article  Google Scholar 

  151. 151.

    Mancini MC, Costa AP, de Melo ME, Cercato C, Giannella-Neto D, Garrido AB, Jr., et al. Effect of gastric bypass on spontaneous growth hormone and ghrelin release profiles. Obesity (Silver Spring) 2006;14 3:383–7.

    CAS  Article  Google Scholar 

  152. 152.

    Cummings DE, Shannon MH. Ghrelin and gastric bypass: is there a hormonal contribution to surgical weight loss? J Clin Endocrinol Metab 2003;88 7:2999–3002.

    PubMed  CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Craig A. Jaffe.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Dimaraki, E.V., Jaffe, C.A. Role of endogenous ghrelin in growth hormone secretion, appetite regulation and metabolism. Rev Endocr Metab Disord 7, 237–249 (2006). https://doi.org/10.1007/s11154-006-9022-0

Download citation

Keywords

  • Ghrelin
  • Somatotropin
  • Growth
  • Obesity
  • Feeding
  • Fasting
  • Appetite
  • Neuropeptides
  • Stomach
  • Review