Ghrelin

Öz

Ghrelin is an acylated polypeptide hormone secreted predominantly by endocrine X (A) cells of the stomach. It acts as a regulator for GH release, energy balance, food intake and body weight. Ghrelin is a 28- amino acid peptide with an essential fatty acid modification at 3aa. And according to this modification it termed as ‘acyl ghrelin’ or ‘des-acyl ghrelin’. The biological active one is ‘acyl ghrelin’. Ghrelin shows it’s effects by binding to it’s special receptor, GH secretagoque receptor (GHS-R). Although primarily expressed in stomach, ghrelin also determined in different tissues such as intestine, heart, kidney, liver, lung, pancreas and placenta. Ghrelin which stimulates the secretion of growth hormone, has an effective role nearly on whole tissues that has a growth ability like bone, cartilage and muscle. 

Anahtar Kelimeler

• Ghrelin
• ghrelin receptor
• ghrelin synthesis

Ghrelin

Öz

Ghrelin, öncelikli olarak midedeki endokrin X(A) hücreleri tarafından salgılanan polipeptid yapıda bir hormondur. Ghrelin, büyüme hormonunun salınımı, enerji dengesi, besin alımı ve vücut ağırlığının ayarlanmasında görev alır. 28 aminoasitten oluşan moleküler yapısında, 3. aminoasite bir yağ asidinin bağlanıp bağlanmamasına göre açillenmiş ya da des-açil ghrelin olarak adlandırılan 2 formu bulunur. Aktif olan, yağ asidi bağlanmış, açillenmiş formudur. Bu formdaki ghrelin etkisini özellikle kendisine özgü olan büyüme hormonu salgılatı- cı reseptöre bağlanarak gösterir. Ghrelinin, büyük oranda sentezi midede gerçekleşmesine rağmen bağırsak, kalp, böbrek, karaciğer, akciğer, pankreas, plasenta gibi birçok organda varlığı tespit edilmiştir. Büyüme hormonu salgılatıcı hormonun salınımını uyaran ghrelin başta kemik, kıkırdak, kas olmak üzere vücudun büyüme yetene- ğinde olan hemen bütün dokuları üzerinde etkin bir role sahiptir.

Anahtar Kelimeler

• Ghrelin
• ghrelin reseptörü
• ghrelin sentezi

Kaynakça

1. Angeloni SV., Glynn N., Ambrosini G., Garant MJ., Higley JD., Suomi S., Hansen BC., 2004. Characterization of the rhesus monkey ghrelin ge- ne and factors influencing grelin gene expression and fasting plasma levels. Endocrinology, 145 (5), 2197-2205.
2. Ariyasu H., Takaya K., Tagami T., Ogawa Y., Hosoda K., Akamizu T., Suda M., Koh T., Natsui K., Toyooka S., Shirakami G., Usui T., Shimatsu A., Doi K., Hosoda H., Kojima M., Kangawa K., Nakao K., 2001. Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans. J Clin Endocrinol Metab., 86, 4753- 4758.
3. Arvat E., Di Vito L., Broglio F., Papotti M., Muccioli G., Dieguez C., Casanueva FF., Deghenghi R., Camanni F., Ghigo E., 2000. Preliminary evidence that Grelin, the natural GH secretagogue (GHS)-receptor ligand, strongly stimulates GH secretion in humans. J Endocrinol Invest., 23 (8), 493-495.
4. Aydın S., Halifeoğlu I., Özercan IH., Erman F., Kılıç N., İlhan N., Ozkan Y., Akpolat N., Sert L., Çaylak E., 2005. A comparison of leptin and grelin levels in plasma and saliva of young healthy subjects. Peptides, 26, 647-652.
5. Aydın S., Özkan Y., Çaylak E., Aydın S., 2006. Ghrelin and its biochemical functions. Türkiye Klinikleri, J Med Sci., 26, 272-283.
6. Baker J., Hardy MP., Zhou J., Bondy C., Lupu F., Bellve AR., Efstratiadis A., 1996. Effects of an igf1 gene null mutation on mouse reproduction. Mol Endocrinol., 10, 903-18.
7. Barreiro ML., Tena-Sempere M., 2004. Ghrelin and reproduction: a novel signal linking energy status and fertility?. Molecular and Cellular Endocrinology, 226, 1–9.
8. Bordi C., Dadda T., Azzoni C., Ferraro G., 2000. Classification of gastric endocrine cells at the light and electron microscopical levels. Microsc. Res. Techn. 48, 258–271.

9. Broglio F., Van Koetsveld P., Benso A., Gottero C., Prodam F., Papotti M., Muccioli G., Gauna C., Hofland L., Deghenghı R., Arvat E., Van Der Lely AJ., Ghigo E., 2002. Ghrelin Secretion is Inhibited by Either Somatostatin or Cortistatin in Humans. The Journal of Clinical Endocrinology & Metabolism, 87(10), 4829-4832.
10. Caminos Je., Gualillo O., Lago F., Otero M., Blanco M., Gallego R., Garcia-Caballero T., Goldring MB., Casanueva FF., Gomez-Reino JJ., Dieguez C., 2005. The endogenous growth hormone secretagogue (ghrelin) is synthesized and secreted by chondrocytes. Endocrinology, 146 (3), 1285-1292.
11. Capella C., Vassallo G., Solcia E., 1971. Light and electron microscopic identification of the histamine-storing argyrophil (ECL) cell in murine stomach and of its equivalent in other mammals. Cell and Tissue Research, 118, 68–84.
12. Cassoni P., Papotti M., Ghe C., Catapano F., Sapino A., Graziani A., Deghenghi R., Reissmann T., Ghigo E., Muccioli G., 2001. 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. J Clin Endocrinol Metab., 86, 1738-1745.
13. Ciampani T., Fabbri A., Isidori A., Dufau ML., 1992. Growth hormone-releasing hormone is produced by rat Leydig cell in culture and acts as a positive regulator of Leydig cell function. Endocrinology, 131, 2785–2792.
14. Clark JT., Karla PS., Crowley WR., Karla SP., 1984. Neuropeptide Y and human pancreatic polypeptide stimulate feeding behaviour in rats. Endocrinology, 115: 427-429.
15. Cowley MA., Smith RG., Diano S., 2003. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic cir- cuit regulating energy homeostasis. Neuron, 37, 649–661.
16. Cummings E., Purnell JQ., Frayo SR., 2001. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes, 50, 1714-1719.
17. Date Y., Kojima M., Hosoda H., Sawaguchi A., Mondal MS., Suganuma T., Matsukura S., Kangawa K., Nakazato M., 2000. Grelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology, 141 (11), 4255-4261.
18. Date Y., Murakami N., Kojima M., Kuroiwa T., Matsukura S., Kangawa K., Nakazato M., 2000. Central effects of a novel acylated peptide, grelin, on growth hormone release in rats. Biochem Biophys Res Commun., 275 (2), 477-480.
19. Date Y., Murakami N., Toshinai K., Matsukura S., Niijima A., Matsuo H., Kangawa K., Nakazato M., 2002. The role of the gastric afferent vagal nerve in grelin-induced feeding and growth hormone secretion in rats. Gastroenterology, 123 (4), 1120-1128.
20. Davis Jc., 1954. The relation between the pancreatic alpha cells and certain cells in the gastric mucosa. J Pathol Bacteriol., 67 (1), 237- 240.
21. De Ambrogi M., Volpe S., Tamanini C., 2003. Ghrelin: central and peripheral effects of a novel peptydil hormone. Med Sci Monit., 9, 217-224.
22. Dornonville De La Cour C., Lindstrom E., Norlen P., Hakanson R., 2004. Ghrelin stimulates gastric emptying but is without effect on acid secretion and gastric endocrine cells. Regul Pept.,120, 23- 32.
23. Druce M., Bloom SR., 2003. Central regulators of food intake. Curr Opin Clin Nutr Metab Care, 6, 361-367.
24. Dzaja A., Dalal Mac., Himmerich H., Uhr M., Pollmacher T., Schuld A., 2004. Sleep enhances nocturnal plasma ghrelin levels in healthy subjects. Am J Physiol Endocrinol Metab., 286, 963-967.
25. Fernandez-Fernandez R., Tena-Sempere M., Aguilar E., Pinilla L., 2004. Ghrelin effects on gonadotropin secretion in male and female rats. Neuroscience Letters, 362, 103–107.
26. Furuta M., Funabashi T., Kimura F., 2001. Intracerebroventricular administration of ghrelin rapidly suppresses pulsatile luteinizing hormone secretion in ovariectomized rats. Biochemical and Biophysical Research Communications, 288, 780- 785.
27. Gaytan F., Barreiro ML., Caminos JE., Chopin LK., Herington AC., Morales C., Pinilla L., Paniagua R., Nistal M., Casanueva FF., Aguilar E., Dieguez C., Tena-Sempere M., 2004. Expression of Ghrelin and Its Functional Receptor, the Type 1a Growth Hormone Secretagogue Receptor, in Normal Human Testis and Testicular Tumors. The Journal of Clinical Endocrinology & Metabolism, 89(1), 400–409.
28. Gnanapavan S., Kola B., Bustin SA., Morris DG., McGee P., Fairclough P., Bhattacharya S., Carpenter R., Grossman AB., Korbonits M. 2002. The tissue distribution of the mRNA of grelin and nsubtypes of its receptor, GHS-R, in humans. Clin Endocrinol Metab., 87, 2988-2991.
29. Groschl M., Topf HG., Bohlender J., 2005. Identification of ghrelin in human saliva: Production by the salivary glands and potential ro- le in proliferation of oral keratinocytes. Clin Chem., 51, 997-1006.
30. Hataya Y., Akamizu T., Takaya K., Kanamoto N., Ariyasu H., Saijo M., Moriyama K., Shimatsu A., Kojima M., Kangawa K., Nakao K., 2001. A low dose of ghrelin stimulates growth hormone (GH) release synergistically with GH-releasing hormone in humans. J Clin Endocrinol Metab., 86, 552-4555.
31. Hoffmann K., 2000. A superfamily of membran- bound O_acyltransferases with implications for WNT signaling. Trends. Biochem. Sci., 25, 111- 112.
32. Kaiya H., Van Der Geyten S., Kojima M., Hosoda H., Kitajima Y., Matsumoto M., Geelissen S., Darras VM., Kangawa K., 2002. Chicken grelin: purification, cDNA cloning, and biological activity. Endocrinology, 143 (9), 3454-3463.
33. Kaiya H., Kojima M., Hosoda H., Moriyama S., Takahashi A., Kawauchi H., Kangawa K., 2003. Peptide purification, complementary deoxyribonucleic acid (DNA) and genomic DNA cloning, and functional characterization of grelin in rainbow trout. Endocrinology, 144 (12), 5215- 5226.
34. Karbonits M, Goldstone AP., 2004. Gueorguiev M., Grossman AB., Ghrelin-a hormone with multiple functions. Front in Neuroend., 25, 27-68.
35. Kojima M., Hosoda H., Date Y., Nakazato M., Matsuo H., Kangawa K., 1999. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature, 402, 656-660.
36. Kojima M., Hosoda H., Matsuo H., Kangawa K., 2001. Ghrelin: discovery of the natural endogenous ligand for the growth hormone secretagogue receptor. Trends. Endocrinol. Metab., 12, 118–122.
37. Kojima M., Kangawa K., 2005. Ghrelin: structure and function, Physiol Rev., 85, 495-522.
38. Kress M., Guthman C., Averbeck B., Reeh PW., 1999. Calsitonin gene related peptid and prostaglandin E 2 but not substance P release induced by antidromic nevre stimulation from rat skin in vitro. Neuroscience, 89, 303 – 310.
39. Litwack G., 2008. Ghrelin, Ed: Gerald Litwack, Vol:77, Elsiver, USA, Pp: 13-25.
40. Lu D, Willard D, Patel IR, 1994. Aou protein is an antagonist of the melanocyte- stimulating- hormone receptor. Nature, 371: 799-802.
41. Lu S., Guan JL., Wang QP., Uehara K., Yamada S., Goto N., Date Y., Nakazato M., Kojima M., Kangawa K., Shioda S., (2002). Immunocytochemical observation of ghrelin- containing neurons in the rat arcuate nucleus. Neuroscience Letters, 321, 157–160.
42. McKee KK., Palyha OC., Feighner SD., Hreniuk DL., Tan CP., Phillips MS., Smith RG., Van der Ploeg LHT., Howard AD., 1997. Molecular analysis of rat pituitary and hypothalamic growth hormone secretagogue receptors. Molecular Endocrinology, 11, 415–423.
43. Miller DW., Harrison JL., Brown YA., Doyle U., Lindsay A., Adam CL., Lea RG., 2005. Immunohistochemical evidence for an endocrine/paracrine role for ghrelin in the reproductive tissues of sheep. Reproductive Biology and Endocrinology, 3, 60-74.
44. Mitchell SE., Nogueiras R., Rance K., Rayner DV., Wood S., Dieguez C., Williams LM., 2006. Circulating hormones and hypothalamic energy balance: regulatory gene expression in the Lou/C and Wistar rats. J Endocrinol., 190 (3), 571-579.
45. Mori K., Yoshimoto A., Takaya K., Hosoda K., Ariyasu H., Yahata K., Mukoyama M., Sugawara A., Hosoda H., Kojima M., Kangawa K., Nakao K., 2000. Kidney produces a novel acylated peptide, grelin. FEBS Lett., 486 (3), 213-216.
46. Morton GJ., Schwartz MW., 2001. The NPY/AgRP neuron and energy homeostasis. Int J Obesity Relat Metab Disord, 25, 56-62.
47. Nagaya N., Kangawa K. 2003. Ghrelin, a novel growth hormonereleasing peptide, in the treatment of chronic heart failure. Regul Pept., 114 (2-3), 71-77.
48. Papotti M., Ghe C., Cassoni P., Catapano F., Deghanghi R., Ghigo E., Muccioli G., 2000. Growth hormone secratagogue binding sites in peripheral humsan tissues. J. Clin. Endocrinol. Metab., 85, 3803-3807.
49. Peino R., Baldelli R., Rodriguez-Garcia J., Rodriguez-Segade S., Kojima M., Kangawa K., Arvat E., Ghigo E., Dieguez C., Casanueva FF., 2000. Grelin-induced growth hormone secretion in humans. Eur J Endocrinol., 143 (6), 11-14.
50. Qu D, Ludwig DS, Gammeltoft S, 1996. A role for melanin-concentrating hormone in the central regulation feeding behavior. Nature, 380, 243- 247.
51. Rindi G., Necchi V., Savio A., Torsello A., Zoli M., Locatelli V., Raimondo F., Cocchi D., Solcia E., 2002. Characterisation of gastric ghrelin cells in man and other mammals: studies in adult and fetal tissues. Histochem. Cell Biol., 117, 511-519.
52. Rindi G., Torsello A., Locatelli V., Solcia E., 2004. Ghrelin Expression and Actions: A Novel Peptide for an Old Cell Type of the Diffuse Endocrine System. Exp Biol Med., 229, 1007– 1016.
53. Sakurai T, Amemiya A, Ishii M, 1998. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feding behavior. Cell, 92, 573-585.
54. Soriano-Guillen L., Barrios V., Campos-Barros A., Argente J., 2004. Ghrelin levels in obesity and anorexia nervosa: effect of weight reduction or recuperation. J Pediatr., 144, 36-42.
55. Smith RG., Van Der Ploeg LHT., Howard AD., Feighner SD., Cheng K., Hickey GJ., Wyvratt MJ., Fisher MH., Nargund RP., Patchett AA., 1997. Peptidomimetic regulation of growth hormone secretion. Endocr Rev, 18, 621–645.
56. Takaya K., Ariyasu H., Kanamoto N., 2000. Ghrelin strongly stimulates growth hormone release in humans. J Clin Endocrinol Metab., 85, 4908–4911.
57. Tanaka M., Hayashida Y., Iguchi T., Nakao N., Nakai N., 2001. Nakashima K., Organization of the mouse grelin gene and promoter: occurrence of a short noncoding first exon. Endocrinology, 142 (8), 3697-3700.
58. Tena-Sempere M., Pinilla L., Gonzalez LC., Dieguez C., Casanueva FF., Aguilar E., 1999. Leptin inhibits testosterone secretion from adult rat testis in vitro, Journal of Endocrinology. 161(2), 211-218.
59. Tena-Sempere M., Barriero ML, Gonzalez LC., Gaytan F., Zhang FP., Caminos JE., Pinilla L., Casanueva FF., Dieguez C., Aguilar E., 2002. Novel Expression and Functional Role of Ghrelin in Rat Testis. Endocrinology, 143, 717–725.
60. Tena-Sempere M., 2005. Exploring the role of ghrelin as novel regulator of gonadal function. Growth Horm IGF Res., 15, 83-88.
61. Tolle V., Zizzari P., Tomasetto C., Rio MC., Epelbaum J., Bluet-Pajot MT., 2001. In vivo and in vitro effects of ghrelin/motilin-related peptide on growth hormone secretion in the rat. Neuroendocrinology, 73, 54-61.
62. Tschop M., Smiley DL., Heiman ML., 2000. Ghrelin induces adiposity in rodents. Nature, 407, 908–913.
63. Tschop M., Weyer C., Tataranni PA., Devanarayan V., Ravussin E., Heiman ML., 2001. Circulating ghrelin levels are decreased in human obesity. Diabetes, 50, 707–709.
64. Unniappan S., Lin X., Cervini L., Rivier J., Kaiya H., Kangawa K., Peter RE., 2002. Goldfish grelin: molecular characterization of the complementary deoxyribonucleic acid, partial gene structure and evidence for its stimulatory role in food intake. Endocrinology, 143 (10), 4143-4146.
65. Wierup N., Svensson H., Mulder H., Sundler F., 2002. The ghrelin cell: A novel developmentally regulated islet cell in the human pancreas. Regul Pept., 107, 63-69.
66. Wren AM., Small CJ., Ward HL., 2000. The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology, 141, 4325-4328.
67. Wren AM., Seal LJ., Cohen Mac., Brynes AE., Frost GS., Murphy KG., Dhillo WS., Ghatei Mac., Bloom SR., 2001. Grelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab., 86 (12), 5992.
68. Yang J, Brown MS., Liang G., Grishin NV., Goldstein JL., 2008. Identification of the Acyltransferase that Octanoylates Ghrelin, an Appetite-Stimulating Peptide Hormone. Cell, 132, 387–396.
69. Yılmaz B. Hormonlar ve Üreme Fizyolojisi, Bi- rinci basım, Feryal Matbaacılık, Ankara, 1999. Pp: 294-296.