GHRELİN VE METABOLİK ETKİLERİ

Year 2008, Volume: 6 Issue: 3, 105 - 115, 31.07.2008

Dürrin Özlem Dabak Tuncay Kuloğlu

Abstract

Ghrelin,
yakın zamanda keşfedilen, enerji dengesinin düzenlenmesi ve glukoz
metabolizması üzerine etkili bir hormondur.
Günümüzde, ghrelin homologlarının balıklarda, kuşlarda, birçok memelide ve
hatta bitkilerde bulunduğu belirlenmiştir. Ghrelinin insanlarda ve hayvanlarda
güçlü bir büyüme hormonu salgılatıcı aktivite-si vardır. Ghrelin, insanlarda ve
kemiricilerde esas olarak mide mukozasında
yer alan endokrin fonksiyonlara sahip sırasıyla P/D1ve X/A hücreleri tarafından
üretilmektedir. Ancak ghrelinin, hem insan hem de kemirici-lerde mide dışında birçok organda bulunduğu da
bildirilmiştir. Bu derlemede ghrelinin keşfi, doku dağılımı ve fizyolojik
etkileri üzerine yoğunlaşılmıştır.

Keywords

Ghrelin, Büyüme Hormonu Salgılatıcı Reseptör, Ghrelin İmmünreaktif Hücreler

References

• 1. Adeghate E, Ponery AS. Ghrelin stimulates insulin secretion from the pancreas of normal and diabetic rats. J Neuroendocrinol 2002; 14: 555–560.
• 2. Andreis PG, Malendowicz LK, Trejter M, et al. Ghrelin and growth hormone secretagogue receptor are expressed in the rat adrenal cortex: Evidence that ghrelin stimulates the growth, but not the secretory activity of adrenal cells. FEBS Lett 2003; 536: 173–179.
• 3. Arvat E, Maccario M, Di Vito L, et al. Endoc-rine activities of ghrelin, a natural growth hormone secretagogue (GHS), in humans: comparison and interactions with hexarelin, a nonnatural peptidyl GHS, and GH-releasing hormone. J Clin Endocrinol Metab 2001; 86: 1169–1174.
• 4. Asakawa A, Inui A, Kaga T, et al. A role of ghrelin in neuroendocrine and behavioral res-ponses to stress in mice. Neuroendocrinology 2001; 74: 143–147.
• 5. Asakawa A, Inui A, Kaga T, et al. Antagonism of ghrelin receptor reduces food intake and body weight gain in mice. Gut. 2003; 52: 947–952.
• 6. Aydın S. Grelin hormonunun keşfi: Araştırma-ları ve klinik uygulamaları. Türk Biyokimya Dergisi 2007; 32: 76–89.
• 7. Barkan AL, Dimaraki EV, Jessup SK, et al. 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: 2180–2184.
• 8. Beck B, Musse N, Stricker-Krongrad A. Ghrelin, macronutrient intake and dietary preferences in long-evans rats. Biochem Biophys Res Commun 2002; 292:1031–1035.
• 9. Bowers CY, Momany F, Reynolds GA, et al. Structure-activity relationships of a synthetic pentapeptide that specifically releases growth hormone in vitro. Endocrinology 1980;106: 663–667.
• 10. Bowers CY. Unnatural growth hormone-releasing peptide begets natural ghrelin. J Clin Endocrinol Metab 2001; 86: 1464–1469.
• 11. Briatore L, Andraghetti G, Cordera R. Acute plasma glucose increase, but not early insulin response, regulates plasma ghrelin. Eur J Endocrinol 2003; 149: 403–406.
• 12. Broglio F, Arvat E, Benso A, et al. Ghrelin, a natural GH secretagogue produced by the stomach, induces hyperglycemia and reduces insulin secretion in humans. J Clin Endocrinol Metab 2001; 86: 5083–5086.
• 13. Caminos JE, Nogueiras R, Blanco M, et al. Cellular distribution and regulation of ghrelin messenger ribonucleic acid in the rat pituitary gland. Endocrinology 2003; 144: 5089–5097.
• 14. Caminos JE, Tena-Sempere M, Gaytan F, et al. Expression of ghrelin in the cyclic and pregnant rat ovary. Endocrinology 2003; 144: 1594–1602.
• 15. Cao JM, Ong H, Chen C. Effects of ghrelin and synthetic GH secretagogues on the cardiovascular system. Trends Endocrinol Metab 2006; 17: 13–18.
• 16. Carlini VP, Monzon ME, Varas MM, et al. Ghrelin increases anxiety-like behavior and memory retention in rats. Biochem Biophys Res Commun 2002; 299: 739–743.
• 17. Cassoni P, Allia E, Marrocco T, et al. Ghrelin and cortistatin in lung cancer: expression of peptides and related receptors in human primary tumors and in vitro effect on the H345 small cell carcinoma cell line. J Endocrinol Invest 2006; 29: 781–790.
• 18. Chan JL, Bullen J, Lee JH, Yiannakouris N, Mantzoros CS. Ghrelin levels are not regulated by recombinant leptin administration and/or three days of fasting in healthy subjects. J Clin Endocrinol Metab 2004; 89: 335–343.
• 19. Cowley MA, Smith RG, Diano S, et al. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 2003; 37: 649–661.
• 20. Cummings DE, Purnell JQ, Frayo RS, et al. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 2001; 50: 1714–1719.
• 21. Cummings DE, Weigle DS, Frayo RS, et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 2002; 346: 1623–1630.
• 22. Dall R, Kanaley J, Hansen TK, et al. Plasma ghrelin levels during exercise in healthy sub-jects and in growth hormone-deficient patients. Eur J Endocrinol 2002; 147: 65–70.
• 23. Date Y, Kojima M, Hosoda H, , et al. Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology 2000; 141: 4255–4261.
• 24. Date Y, Nakazato M, Hashiguchi S, et al. Gh-relin is present in pancreatic alpha-cells of hu-mans and rats and stimulates insulin secretion. Diabetes 2002; 51: 124–129.
• 25. De Ambrogi M, Volpe S, Tamanini C. Ghrelin: central and peripheral effects of a novel peptydil hormone. Med Sci Monit 2003; 9: 217–224.
• 26. Eden Engström B, Burman P, Holdstock C, Karlsson FA. Effects of growth hormone (GH) on ghrelin, leptin, and adiponectin in GH-deficient patients. J Clin Endocrinol Metab 2003; 88: 5193–5198.
• 27. Edholm T, Levin F, Hellström PM, Schmidt PT. Ghrelin stimulates motility in the small intestine of rats through intrinsic cholinergic neurons. Regul Pept 2004; 121: 25–30.
• 28. Egido EM, Rodriguez-Gallardo J, Silvestre RA, Marco J. Inhibitory effect of ghrelin on insulin and pancreatic somatostatin secretion. Eur J Endocrinol 2002; 146: 241–244.
• 29. Gaytan F, Barreiro ML, Caminos JE, et al. Ex-pression of ghrelin and its functional receptor, the type 1a growth hormone secretagogue receptor, in normal human testis and testicular tumors. J Clin Endocrinol Metab 2004; 89: 400–409.
• 30. Gnanapavan S, Kola B, Bustin SA, et al. The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J Clin Endocrinol Metab 2002; 87: 2988–2991.
• 31. Goldstone AP, Thomas EL, Brynes AE, et al. Elevated fasting plasma ghrelin in prader-willi syndrome adults is not solely explained by their reduced visceral adiposity and insulin resistance. J Clin Endocrinol Metab 2004; 89: 1718–1726.
• 32. Gualillo O, Caminos J, Blanco M, et al. Ghre-lin, a novel placental-derived hormone. Endoc-rinology 2001; 142: 788–794.
• 33. Gualillo O, Caminos JE, Kojima M, et al. Gen-der and gonadal influences on ghrelin mRNA levels in rat stomach. Eur J Endocrinol 2001; 144: 687–690.
• 34. Guan XM, Yu H, Palyha OC, et al. Distribu-tion of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Brain Res Mol Brain Res 1997; 48: 23–29.
• 35. Guyton AC, Hall JE. Tıbbi Fizyoloji. Çavuşoğ-lu H (Çeviri Editörü). 9. Baskı, İstanbul, Nobel Tıp Kitapevleri, 1996: 315–319.
• 36. Hakanson R, Ekelund M, Sundler F. Activa-tion and proliferation of gastric endocrine cells. In: Falkmer S, Hakanson R, Sundler F (eds) Evolution and Tumor Pathology of the Neuroendocrine System. Elsevier, Amsterdam, 1984: 371–398.
• 37. Haqq AM, Farooqi IS, O'Rahilly S, et al. Serum ghrelin levels are inversely correlated with body mass index, age, and insulin con-centrations in normal children and are markedly increased in Prader-Willi syndrome. J Clin Endocrinol Metab 2003; 88: 174–178.
• 38. Hayashida T, Nakahara K, Mondal MS, et al. Ghrelin in neonatal rats: distribution in stomach and its possible role. J Endocrinol. 2002; 173: 239–245.
• 39. Herrington J, Hile B. Growth hormone-relea-sing hexapeptide elevates intracellular calcium in rat somatotropes by two mechanisms. Endocrinology 1994; 135: 1100–1108.
• 40. Hosoda H, Kojima M, Kangawa K. Biological, physiological, and pharmacological aspects of ghrelin. J Pharmacol Sci 2006; 100: 398–410.
• 41. Howard AD, Feighner SD, Cully DF, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 1996; 273: 974–977.
• 42. Inui A, Asakawa A, Bowers CY, Mantovani G, Laviano A, Meguid MM, Fujimiya M. Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ. FASEB J. 2004 Mar;18(3):439-56.
• 43. Ishii S, Kamegai J, Tamura H, et al. Role of ghrelin in streptozotocin-induced diabetic hyperphagia. Endocrinology 2002; 143: 4934–4937.
• 44. Itoh FT, Komatsu T, Kushibiki S, Hodate K. Effects of ghrelin injection on plasma con-centrations of glucose, pancreatic hormones and cortisol in Holstein dairy cattle. Comp Biochem Physiol A Mol Integr Physiol 2006; 143: 97–102.
• 45. Janssen JA, van der Toorn FM, Hofland LJ, et al. Systemic ghrelin levels in subjects with growth hormone deficiency are not modified by one year of growth hormone replacement therapy. Eur J Endocrinol 2001; 145:711–716.
• 46. Jarkovska Z, Hodkova M, Sazamova M, , et al. Plasma levels of active and total ghrelin in renal failure: a relationship with GH/IGF-I axis. Growth Horm IGF Res 2005;15: 369–376.
• 47. Kageyama H, Funahashi H, Hirayama M, et al. Morphological analysis of ghrelin and its receptor distribution in the rat pancreas. Regul Pept 2005; 126: 67–71.
• 48. Kamegai J, Tamura H, Shimizu T, et al. Effects of insulin, leptin, and glucagon on ghrelin secretion from isolated perfused rat stomach. Regul Pept 2004;15;119: 77–81.
• 49. Kamegai J, Tamura H, Shimizu T, et al. Insulin-like growth factor-I down-regulates ghrelin receptor (growth hormone secretago-gue receptor) expression in the rat pituitary. Regul Pept 2005; 15: 203–206.
• 50. Kamegai J, Tamura H, Shimizu T, et al. Regulation of the ghrelin gene: growth hormo-ne-releasing hormone upregulates ghrelin mRNA in the pituitary. Endocrinology 2001; 142: 4154–4157.
• 51. Katugampola SD, Pallikaros Z, Davenport AP. [125I-His(9)]-ghrelin, a novel radioligand for localizing GHS orphan receptors in human and rat tissue: up-regulation of receptors with athersclerosis. Br J Pharmacol 2001; 134: 143–149.
• 52. Kim SW, Her SJ, Park SJ, et al. Ghrelin stimulates proliferation and differentiation and inhibits apoptosis in osteoblastic MC3T3-E1 cells. Bone 2005; 37: 359–369.
• 53. 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: 3581–3586.
• 54. Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999; 402: 656–660.
• 55. Kojima M, Hosoda H, Kangawa K. Clinical endocrinology and metabolism. Ghrelin, a novel growth-hormone-releasing and appetite-stimulating peptide from stomach. Best Pract Res Clin Endocrinol Metab 2004;18: 517–530.
• 56. Kojima M, Hosoda H, Matsuo H, Kangawa K. Ghrelin: discovery of the natural endogenous ligand for the growth hormone secretagogue receptor. Trends Endocrinol Metab 2001;12: 118–122.
• 57. Kojima M, Kangawa K. Ghrelin: structure and function. PhysiolRev 2005; 85: 495–522.
• 58. Korbonits M, Goldstone AP, Gueorguiev M, Grossman AB. "Ghrelin--a hormone with multiple functions." Front Neuroendocrinol. 2004; 25: 27–68.
• 59. Leal-Cerro A, Torres E, Soto A, et al. Ghrelin is no longer able to stimulate growth hormone secretion in patients with Cushing's syndrome but instead induces exaggerated corticotropin and cortisol responses. Neuroendocrinology 2002; 76: 390–396.
• 60. Lee HM, Wang G, Englander EW, Kojima M, Greeley GH Jr. Ghrelin, a new gastrointestinal endocrine peptide that stimulates insulin secretion: enteric distribution, ontogeny, influence of endocrine, and dietary manipulations. Endocrinology 2002; 143:185–190.
• 61. Levin F, Edholm T, Ehrström M, et al. Effect of peripherally administered ghrelin on gastric emptying and acid secretion in the rat. Regul Pept 2005; 131: 59–65.
• 62. Liu YL, Yakar S, Otero-Corchon V, Low MJ, Liu JL. Ghrelin gene expression is age-dependent and influenced by gender and the level of circulating IGF-I. Mol Cell Endocrinol 2002; 189: 97–103.
• 63. Marchesini G, Pagotto U, Bugianesi E, et al. Low ghrelin concentrations in nonalcoholic fatty liver disease are related to insulin resistance. J Clin Endocrinol Metab 2003; 88: 5674–5679.
• 64. Masaoka T, Suzuki H, Hosoda H, et al. Enhanced plasma ghrelin levels in rats with streptozotocin-induced diabetes. FEBS Lett 2003; 541: 64–68.
• 65. Masuda Y, Tanaka T, Inomata N, et al. Ghrelin stimulates gastric acid secretion and motility in rats. Biochem Biophys Res Commun 2000; 276: 905–908.
• 66. McCowen KC, Maykel JA, Bistrian BR, Ling PR. Circulating ghrelin concentrations are lowered by intravenous glucose or hyperinsulinemic euglycemic conditions in rodents. J Endocrinol 2002; 175: 7–11.
• 67. McKee KK, Palyha OC, Feighner SD, et al. Molecular analysis of rat pituitary and hypothalamic growth hormone secretagogue receptors. Mol Endocrinol 1997; 11: 415–423.
• 68. Momany FA, Bowers CY, Reynolds GA, et al. Design, synthesis, and biological activity of peptides which release growth hormone in vitro. Endocrinology 1981; 108: 31–39.
• 69. Mori K, Yoshimoto A, Takaya K, et al. Kidney produces a novel acylated peptide, ghrelin. FEBS Lett 2000; 486: 213–216.
• 70. Muccioli G, Tschöp M, Papotti M, , et al. Neuroendocrine and peripheral activities of ghrelin: implications in metabolism and obesity. Eur J Pharmacol 2002; 440: 235–254.
• 71. Muller AF, Janssen JA, Hofland LJ, et al. Blockade of the growth hormone (GH) receptor unmasks rapid GH-releasing peptide–6-mediated tissue-specific insulin resistance. J Clin Endocrinol Metab 2001; 86: 590–593.
• 72. Muller AF, Lamberts SW, Janssen JA, et al. Ghrelin drives GH secretion during fasting in man. Eur J Endocrinol 2002; 146: 203–207.
• 73. Nagaya N, Kangawa K. Ghrelin, a novel growth hormone-releasing peptide, in the treatment of chronic heart failure. Regul Pept 2003; 114: 71–77.
• 74. Nagaya N, Kojima M, Uematsu M, et al. Hemodynamic and hormonal effects of human ghrelin in healthy volunteers. Am J Physiol Regul Integr Comp Physiol 2001; 280: 1483–1487.
• 75. Nagaya N, Uematsu M, Kojima M, , et al. Chronic administration of ghrelin improves left ventricular dysfunction and attenuates development of cardiac cachexia in rats with heart failure. Circulation 2001; 104: 1430–1435.
• 76. Nagaya N, Uematsu M, Kojima M, et al. Elevated circulating level of ghrelin in cachexia associated with chronic heart failure: relationships between ghrelin and anabolic / catabolic factors. Circulation 2001; 104: 2034–2038.
• 77. Nakai Y, Hosoda H, Nin K, et al. Plasma levels of active form of ghrelin during oral glucose tolerance test in patients with anorexia nervosa. Eur J Endocrinol 2003; 149: 1–3.
• 78. Nakazato M, Murakami N, Date Y, et al. A role for ghrelin in the central regulation of feeding. Nature 2001; 409: 194–198.
• 79. Pecker F. Ghrelin in the heart and growth hormone: which is chicken, which is egg? Cardiovasc Res 2004; 62: 442–443.
• 80. Pöykkö SM, Kellokoski E, Hörkkö S, et al. Low plasma ghrelin is associated with insulin resistance, hypertension, and the prevalence of type 2 diabetes. Diabetes 2003; 52: 2546–2553.
• 81. Prado CL, Pugh-Bernard AE, Elghazi L, Sosa-Pineda B, Sussel L. Ghrelin cells replace insulin-producing beta cells in two mouse models of pancreas development. Proc Natl Acad Sci U S A 2004; 101: 2924–2929.
• 82. 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: 5747–5752.
• 83. Raffel A, Krausch M, Cupisti K, et al. Ghrelin expression in neuroendocrine tumours of the gastrointestinal tract with multiple endocrine neoplasia type 1. Horm Metab Res 2005; 37: 653-655.
• 84. Riis AL, Hansen TK, Moller N, Weeke J, Jorgensen JO. Hyperthyroidism is associated with suppressed circulating ghrelin levels. J Clin Endocrinol Metab 2003; 88: 853–857.
• 85. Rubinfeld H, Hadani M, Taylor JE, et al. Novel ghrelin analogs with improved affinity for the GH secretagogue receptor stimulate GH and prolactin release from human pituitary cells. Eur J Endocrinol. 2004;151:787–795.
• 86. Sachs G, Zeng N, Prinz C. Physiology of isolated gastric endocrine cells. Annu Rev Physiol 1997; 59: 234–256.
• 87. Sakata I, Nakamura K, Yamazaki M, et al. Ghrelin-producing cells exist as two types of cells, closed- and opened-type cells, in the rat gastrointestinal tract. Peptides 2002; 23: 531–536.
• 88. Sakata I, Tanaka T, Matsubara M, et al. Postnatal changes in ghrelin mRNA expression and in ghrelin-producing cells in the rat stomach J Endocrinol 2002; 174: 463–471.
• 89. Santos M, Bastos P, Gonzaga S, et al. Ghrelin expression in human and rat fetal lungs and the effect of ghrelin administration in nitrofen-induced congenital diaphragmatic hernia. Pediatr Res 2006; 59: 531–537.
• 90. Shimada M, Date Y, Mondal MS, et al. A single intravenous injection of somatostatin reduced the systemic plasma concentration of ghrelin in rats. Somatostatin suppresses ghrelin secretion from the rat stomach. Biochem Biophys Res Commun 2003; 302: 520-525.
• 91. Shimizu Y, Nagaya N, Isobe T, et al. Increased plasma ghrelin level in lung cancer cachexia. Clin Cancer Res 2003; 9: 774–778.
• 92. Shintani M, Ogawa Y, Ebihara 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: 227–232.
• 93. Simonsson M, Eriksson S, Hakanson R, et al. Endocrine cells in the human oxyntic mucosa. A histochemical study. Scand J Gastroenterol 1988; 23: 1089–1099.
• 94. Smith RG, Van der Ploeg LH, Howard AD, et al. Peptidomimetic regulation of growth hormone secretion. Endocr Rev 1997; 18: 621–645.
• 95. 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 U S A. 2004; 101: 4679–4684.
• 96. Tacke F, Brabant G, Kruck E, et al. Ghrelin in chronic liver disease. J Hepatol 2003; 38: 447–454.
• 97. Takaya K, Ariyasu H, Kanamoto N, et al. Ghrelin strongly stimulates growth hormone release in humans. J Clin Endocrinol Metab 2000; 85: 4908–4911.
• 98. Tanaka K, Minoura H, Isobe T, et al. Ghrelin is involved in the decidualization of human endometrial stromal cells. J Clin Endocrinol Metab 2003; 88: 2335–2340.
• 99. Tanaka M, Naruo T, Muranaga T, et al. Increased fasting plasma ghrelin levels in patients with bulimia nervosa. Eur. J. Endocrinol 2002; 146: 1–3.
• 100. Tassone F, Broglio F, Destefanis S, et al. Neuroendocrine and metabolic effects of acute ghrelin administration in human obesity. J Clin Endocrinol Metab 2003; 88: 5478–5483.
• 101. Tschöp M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature 2000; 407: 908–913.
• 102. Tschöp M, Wawarta R, Riepl RL, et al. Post-prandial decrease of circulating human ghrelin levels. J Endocrinol Invest 2001; 24: 19–21.
• 103. Tschöp M, Weyer C, Tataranni PA, et al. Circulating ghrelin levels are decreased in human obesity. Diabetes 2001; 50: 707–709.
• 104. Ueno H, Yamaguchi H, Kangawa K, Nakazato M. Ghrelin: a gastric peptide that regulates food intake and energy homeostasis. Regul Pept 2005;126: 11–19.
• 105. Volante M, Allia E, Fulcheri E, et al. Ghrelin in fetal thyroid and follicular tumors and cell lines: expression and effects on tumor growth. Am J Pathol 2003; 162: 645–654.
• 106. Volante M, Allìa E, Gugliotta P, et al.Expression of ghrelin and of the GH secretagogue receptor by pancreatic islet cells and related endocrine tumors. J Clin Endocrinol Metab 2002; 87: 1300–1308.
• 107. Volante M, Fulcheri E, Allia E, et al. Ghrelin expression in fetal, infant, and adult human lung. J Histochem Cytochem 2002; 50: 1013–1021.
• 108. Wang G, H.M. Lee, E. Englander and G.H. Greeley, Jr. Ghrelin—not just another stomach hormone. Regul. Pept 2002; 105: 75–81.
• 109. Weigle DS, Cummings DE, Newby PD, et al. Roles of leptin and ghrelin in the loss of body weight caused by a low fat, high carbohydrate diet. J Clin Endocrinol Metab 2003; 88: 1577–1586.
• 110. Wiley KE, Davenport AP. Comparison of vasodilators in human internal mammary artery: ghrelin is a potent physiological antagonist of endothelin–1. Br J Pharmacol 2002; 136: 1146–1152.
• 111. Wren AM, Seal LJ, Cohen MA, et al. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 2001; 86: 5992.
• 112. Wren AM, Small CJ, Abbott CR, et al. Ghrelin causes hyperphagia and obesity in rats. Diabetes 2001; 50: 2540–2547.
• 113. Wren AM, Small CJ, Ward HL, et al. The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology 2000; 141: 4325–4328.
• 114. Yabuki A, Taharaguchi S, Ichii O, et al. Immunohistochemical localization of ghrelin in rodent kidneys. Histochem Cell Biol 2006; 126: 231–238.