Horm Metab Res 2009; 41(11): 814-821
DOI: 10.1055/s-0029-1233462
Original Basic

© Georg Thieme Verlag KG Stuttgart · New York

Expression of Ghrelin and its Receptor in Human Tissues

B. Ueberberg1 , N. Unger1 , W. Saeger2 , K. Mann1 , S. Petersenn1
  • 1Department of Endocrinology and Division of Laboratory Research, University of Duisburg-Essen, Essen, Germany
  • 2Institute of Pathology, Marienhospital, Hamburg, Germany
Weitere Informationen

Publikationsverlauf

received 20.03.2008

accepted 22.06.2009

Publikationsdatum:
10. August 2009 (online)

Abstract

Ghrelin is a peptide thought to be involved in the regulation of appetite. Furthermore, significant effects on the release of growth hormone (GH) and ACTH were demonstrated. Contributing to the physiological relevance of this hormone, we investigated the expression of ghrelin and its receptor (GHS-R) in several normal human tissues. RNA samples (BD Biosciences) underwent one-step TaqMan Real-Time RT-PCR. Immunohistochemistry was performed on paraffin-embedded tissues using specific primary antibodies against ghrelin and its receptor. Relevant ghrelin mRNA levels were detected in all human tissues with the highest levels in stomach, pituitary, and small intestine. By immunohistochemistry, ghrelin peptide expression was detectable in reproductive and endocrine organs (ovary, anterior pituitary, adrenal gland), and organs of the gastrointestinal tract (stomach, pancreas). GHS-R1a mRNA expression was demonstrated in 10 of 24 human organs analyzed with the highest levels in pituitary, adrenal gland, and spinal cord. Expression of the receptor peptide was detected by immunohistochemistry in endocrine and reproductive organs (anterior pituitary, thyroid, pancreas, testis), parts of the CNS (cerebrum, cerebellum), and in single cells of bone marrow. Expression of both ghrelin and its receptor in endocrine and reproductive organs may indicate new endocrine or paracrine mechanisms of regulation in these tissues.

References

  • 1 Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach.  Nature. 1999;  402 656-660
  • 2 Date Y, Kojima M, Hosoda H, Sawaguchi A, Mondal MS, Suganuma T, Matsukura S, Kangawa K, Nakazato M. 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
  • 3 Date Y, Nakazato M, Hashiguchi S, Dezaki K, Mondal MS, Hosoda H, Kojima M, Kangawa K, Arima T, Matsuo H, Yada T, Matsukura S. Ghrelin is present in pancreatic alpha-cells of humans and rats and stimulates insulin secretion.  Diabetes. 2002;  51 124-129
  • 4 Gnanapavan S, Kola B, Bustin SA, Morris DG, McGee P, Fairclough P, Bhattacharya S, Carpenter R, Grossman AB, Korbonits M. The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans.  J Clin Endocrinol Metab. 2002;  87 2988
  • 5 Gualillo O, Caminos J, Blanco M, Garcia-Caballero T, Kojima M, Kangawa K, Dieguez C, Casanueva F. Ghrelin, a novel placental-derived hormone.  Endocrinology. 2001;  142 788-794
  • 6 Hattori N, Saito T, Yagyu T, Jiang BH, Kitagawa K, Inagaki C. GH, GH receptor, GH secretagogue receptor, and ghrelin expression in human T cells, B cells, and neutrophils.  J Clin Endocrinol Metab. 2001;  86 4284-4291
  • 7 Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, Hamelin M, Hreniuk DL, Palyha OC, Anderson J, Paress PS, Diaz C, Chou M, Liu KK, McKee KK, Pong SS, Chaung LY, Elbrecht A, Dashkevicz M, Heavens R, Rigby M, Sirinathsinghji DJ, Dean DC, Melillo DG, Patchett AA, Nargund R, Griffin PR, DeMartino JA, Gupta SK, Schaeffer JM, Smith RG, Van der Ploeg LH. A receptor in pituitary and hypothalamus that functions in growth hormone release.  Science. 1996;  273 974-977
  • 8 Korbonits M, Kojima M, Kangawa K, Grossman AB. Presence of ghrelin in normal and adenomatous human pituitary.  Endocrine. 2001;  14 101-104
  • 9 Mori K, Yoshimoto A, Takaya K, Hosoda K, Ariyasu H, Yahata K, Mukoyama M, Sugawara A, Hosoda H, Kojima M, Kangawa K, Nakao K. Kidney produces a novel acylated peptide, ghrelin.  FEBS Lett. 2000;  486 213-216
  • 10 Tena-Sempere M, Barreiro ML, Gonzalez LC, Gaytan F, Zhang FP, Caminos JE, Pinilla L, Casanueva FF, Dieguez C, Aguilar E. Novel expression and functional role of ghrelin in rat testis.  Endocrinology. 2002;  143 717-725
  • 11 Arvat E, Maccario M, Di Vito L, Broglio F, Benso A, Gottero C, Papotti M, Muccioli G, Dieguez C, Casanueva FF, Deghenghi R, Camanni F, Ghigo E. Endocrine activities of ghrelin, a natural growth hormone secretagogue (GHS), in humans: comparison and interactions with hexarelin, a non-natural peptidyl GHS, and GH-releasing hormone.  J Clin Endocrinol Metab. 2001;  86 1169-1174
  • 12 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 4570-4582
  • 13 Takaya K, Ariyasu H, Kanamoto N, Iwakura H, Yoshimoto A, Harada M, Mori K, Komatsu Y, Usui T, Shimatsu A, Ogawa Y, Hosoda K, Akamizu T, Kojima M, Kangawa K, Nakao K. Ghrelin strongly stimulates growth hormone release in humans.  J Clin Endocrinol Metab. 2000;  85 4908-4911
  • 14 Broglio F, Arvat E, Benso A, Gottero C, Muccioli G, Papotti M, van der Lely AJ, Deghenghi R, Ghigo E. 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
  • 15 Lee HM, Wang G, Englander EW, Kojima M, Greeley  Jr GH. Ghrelin, a new gastrointestinal endocrine peptide that stimulates insulin secretion: enteric distribution, ontogeny, influence of endocrine, and dietary manipulations.  Endocrinology. 2002;  143 185-190
  • 16 Murata M, Okimura Y, Iida K, Matsumoto M, Sowa H, Kaji H, Kojima M, Kangawa K, Chihara K. Ghrelin modulates the downstream molecules of insulin signaling in hepatoma cells.  J Biol Chem. 2002;  277 5667-5674
  • 17 Nagaya N, Kojima M, Uematsu M, Yamagishi M, Hosoda H, Oya H, Hayashi Y, Kangawa K. Hemodynamic and hormonal effects of human ghrelin in healthy volunteers.  Am J Physiol Regul Integr Comp Physiol. 2001;  280 R1483-R1487
  • 18 Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, Dhillo WS, Ghatei MA, Bloom SR. Ghrelin enhances appetite and increases food intake in humans.  J Clin Endocrinol Metab. 2001;  86 5992
  • 19 Muccioli G, Baragli A, Granata R, Papotti M, Ghigo E. Heterogeneity of ghrelin/growth hormone secretagogue receptors.  Toward the understanding of the molecular identity of novel ghrelin/GHS receptors. Neuroendocrinology. 2007;  86 147-164
  • 20 McKee KK, Palyha OC, Feighner SD, Hreniuk DL, Tan CP, Phillips MS, Smith RG, Van der Ploeg LH, Howard AD. Molecular analysis of rat pituitary and hypothalamic growth hormone secretagogue receptors.  Mol Endocrinol. 1997;  11 415-423
  • 21 Yokote R, Sato M, Matsubara S, Ohye H, Niimi M, Murao K, Takahara J. Molecular cloning and gene expression of growth hormone-releasing peptide receptor in rat tissues.  Peptides. 1998;  19 15-20
  • 22 Guan XM, Yu H, Palyha OC, McKee KK, Feighner SD, Sirinathsinghji DJ, Smith RG, Van der Ploeg LH, Howard AD. Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues.  Brain Res Mol Brain Res. 1997;  48 23-29
  • 23 Jeffery PL, Herington AC, Chopin LK. Expression and action of the growth hormone releasing peptide ghrelin and its receptor in prostate cancer cell lines.  J Endocrinol. 2002;  172 R7-R11
  • 24 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 USA. 2004;  101 4679-4684
  • 25 Papotti M, Cassoni P, Volante M, Deghenghi R, Muccioli G, Ghigo E. Ghrelin-producing endocrine tumors of the stomach and intestine.  J Clin Endocrinol Metab. 2001;  86 5052-5059
  • 26 Papotti M, Ghe C, Cassoni P, Catapano F, Deghenghi R, Ghigo E, Muccioli G. Growth hormone secretagogue binding sites in peripheral human tissues.  J Clin Endocrinol Metab. 2000;  85 3803-3807
  • 27 Ueberberg B, Unger N, Sheu SY, Walz MK, Schmid KW, Saeger W, Mann K, Petersenn S. Differential expression of ghrelin and its receptor (GHS-R1a) in various adrenal tumors and normal adrenal gland.  Horm Metab Res. 2008;  40 181-188
  • 28 Carraro G, Albertin G, Abudukerimu A, Aragona F, Nussdorfer GG. Growth hormone secretagogue receptor subtypes 1a and 1b are expressed in the human adrenal cortex.  Int J Mol Med. 2004;  13 295-298
  • 29 Tortorella C, Macchi C, Spinazzi R, Malendowicz LK, Trejter M, Nussdorfer GG. Ghrelin, an endogenous ligand for the growth hormone-secretagogue receptor, is expressed in the human adrenal cortex.  Int J Mol Med. 2003;  12 213-217
  • 30 Volante M, Allia E, Gugliotta P, Funaro A, Broglio F, Deghenghi R, Muccioli G, Ghigo E, Papotti M. 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
  • 31 Korbonits M, Bustin SA, Kojima M, Jordan S, Adams EF, Lowe DG, Kangawa K, Grossman AB. The expression of the growth hormone secretagogue receptor ligand ghrelin in normal and abnormal human pituitary and other neuroendocrine tumors.  J Clin Endocrinol Metab. 2001;  86 881-887
  • 32 Kamegai J, Tamura H, Shimizu T, Ishii S, Tatsuguchi A, Sugihara H, Oikawa S, Kineman RD. 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 3731-3738
  • 33 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
  • 34 Kanamoto N, Akamizu T, Hosoda H, Hataya Y, Ariyasu H, Takaya K, Hosoda K, Saijo M, Moriyama K, Shimatsu A, Kojima M, Kangawa K, Nakao K. Substantial production of ghrelin by a human medullary thyroid carcinoma cell line.  J Clin Endocrinol Metab. 2001;  86 4984-4990
  • 35 Raghay K, Garcia-Caballero T, Nogueiras R, Morel G, Beiras A, Dieguez C, Gallego R. Ghrelin localization in rat and human thyroid and parathyroid glands and tumours.  Histochem Cell Biol. 2006;  125 239-246
  • 36 Volante M, Allia E, Fulcheri E, Cassoni P, Ghigo E, Muccioli G, Papotti M. Ghrelin in fetal thyroid and follicular tumors and cell lines: expression and effects on tumor growth.  Am J Pathol. 2003;  162 645-654
  • 37 Gaytan F, Barreiro ML, Chopin LK, Herington AC, Morales C, Pinilla L, Casanueva FF, Aguilar E, Dieguez C, Tena-Sempere M. Immunolocalization of ghrelin and its functional receptor, the type 1a growth hormone secretagogue receptor, in the cyclic human ovary.  J Clin Endocrinol Metab. 2003;  88 879-887
  • 38 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. Expression 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
  • 39 Bennett PA, Thomas GB, Howard AD, Feighner SD, van der Ploeg LH, Smith RG, Robinson IC. Hypothalamic growth hormone secretagogue-receptor (GHS-R) expression is regulated by growth hormone in the rat.  Endocrinology. 1997;  138 4552-4557
  • 40 Katayama M, Nogami H, Nishiyama J, Kawase T, Kawamura K. Developmentally and regionally regulated expression of growth hormone secretagogue receptor mRNA in rat brain and pituitary gland.  Neuroendocrinology. 2000;  72 333-340
  • 41 Kim MS, Yoon CY, Park KH, Shin CS, Park KS, Kim SY, Cho BY, Lee HK. Changes in ghrelin and ghrelin receptor expression according to feeding status.  Neuroreport. 2003;  14 1317-1320
  • 42 Kojima M, Hosoda H, Kangawa K. Purification and distribution of ghrelin: the natural endogenous ligand for the growth hormone secretagogue receptor.  Horm Res. 2001;  56 ((Suppl 1)) 93-97
  • 43 Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, Matsukura S. A role for ghrelin in the central regulation of feeding.  Nature. 2001;  409 194-198
  • 44 Shintani M, Ogawa Y, Ebihara K, Aizawa-Abe M, Miyanaga F, Takaya K, Hayashi T, Inoue G, Hosoda K, Kojima M, Kangawa K, Nakao K. 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
  • 45 Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents.  Nature. 2000;  407 908-913
  • 46 Wren AM, Small CJ, Ward HL, Murphy KG, Dakin CL, Taheri S, Kennedy AR, Roberts GH, Morgan DG, Ghatei MA, Bloom SR. The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion.  Endocrinology. 2000;  141 4325-4328
  • 47 Volante M, Fulcheri E, Allia E, Cerrato M, Pucci A, Papotti M. Ghrelin expression in fetal, infant, and adult human lung.  J Histochem Cytochem. 2002;  50 1013-1021
  • 48 Yabuki A, Taharaguchi S, Ichii O, Kojima M, Nishi Y, Mifune H, Kamimura R, Matsumoto M, Suzuki S. Immunohistochemical localization of ghrelin in rodent kidneys.  Histochem Cell Biol. 2006;  126 231-238
  • 49 Guebre-Egziabher F, Bernhard J, Geelen G, Malvoisin E, Hadj-Aissa A, Fouque D. Leptin, adiponectin, and ghrelin dysregulation in chronic kidney disease.  J Ren Nutr. 2005;  15 116-120
  • 50 Iglesias MJ, Pineiro R, Blanco M, Gallego R, Dieguez C, Gualillo O, Gonzalez-Juanatey JR, Lago F. Growth hormone releasing peptide (ghrelin) is synthesized and secreted by cardiomyocytes.  Cardiovasc Res. 2004;  62 481-488
  • 51 Enomoto M, Nagaya N, Uematsu M, Okumura H, Nakagawa E, Ono F, Hosoda H, Oya H, Kojima M, Kanmatsuse K, Kangawa K. Cardiovascular and hormonal effects of subcutaneous administration of ghrelin, a novel growth hormone-releasing peptide, in healthy humans.  Clin Sci (Lond). 2003;  105 431-435
  • 52 Frascarelli S, Ghelardoni S, Ronca-Testoni S, Zucchi R. Effect of ghrelin and synthetic growth hormone secretagogues in normal and ischemic rat heart.  Basic Res Cardiol. 2003;  98 401-405
  • 53 Nagaya N, Moriya J, Yasumura Y, Uematsu M, Ono F, Shimizu W, Ueno K, Kitakaze M, Miyatake K, Kangawa K. Effects of ghrelin administration on left ventricular function, exercise capacity, and muscle wasting in patients with chronic heart failure.  Circulation. 2004;  110 3674-3679

Correspondence

Prof. Dr. med. S. Petersenn

Department of Endocrinology and Division of Laboratory Research

University of Duisburg-Essen

Hufelandstr. 55

45122 Essen

Telefon: +49 201 723 2854

Fax: +49 201 723 5976

eMail: stephan.petersenn@uni-due.de