Grelinin yapısı ve organizmadaki fonksiyonları

Grelin, 1999 yılında Masayasu Kojima tarafından tanımlanmış bir hormondur. 28 aminoasitten oluşmuş bir polipeptiddir. Dolaşımdaki grelin miktarının önemli bir kısmı mideden salgılanır ve biyolojik olarak aktif olabilmesi için üçüncü aminoasidi olan serin kalıntısına n-oktanoik asit bağlanması gereklidir. Grelin, reseptörü olan GHSR1a'a bağlanarak hücreiçi Ca konsantrasyonlarını arttırır, büyüme hormonu (GH) salgılanmasına neden olur ve birçok fizyolojik etkisini bu yolla gösterir. Grelin, hipotalamik arkuat nükleusa etki ederek, gıda alımını kontrol eder; açlıkta grelin düzeyleri yükselir, yemek yemeyi takiben düşer. Oreksijenik etkilidir ve leptine zıt etki gösterdiği bildirilmiştir. Açillenmemiş (n-oktanoik asit bağlanmamış) grelinin de biyolojik fonksiyonları olduğu düşünülmektedir; ancak henüz bağlandığı reseptör ve etki mekanizması tanımlanmamıştır. Açillenmemiş grelinin; hücre proliferasyonunda, lipolizde, adipogenezde ve kardivaskuler fonksiyonlarda etkili olduğu düşünülmektedir. Fizyolojik ve patolojik değişimlerde, grelin düzeylerinin azaldığı veya arttığı bildirilmiştir. Obezlerde ve tip 2 diyabetli kişilerde de grelin düzeylerinin düşük olduğu gösterilmiştir. Grelin salgılanması sirkadyen ritm gösterir; özellikle sabaha karşı 2 saatlerinde dolaşımdaki grelin miktarı en yüksek düzeydedir. Önümüzdeki dönemlerde yapılacak çalışmaların grelinin birçok bilinmeyen fonksiyonuna ve özellikle açillenmemiş grelinin biyolojik etkilerine ışık tutacağı düşünülmektedir.

Ghrelin: Structure and biological functions

Ghrelin, a 28 amino acid peptide hormone discovered in 1999 by Kojima et al., is an endogenous ligand for the growth hormone secretagogue (GHS) receptor. It is secreted mainly by the stomach and n-octanoylation at the third serine residue of this peptide is essential for its bioactivity. Ghrelin stimulates growth hormone release, increases intracellular calcium concentration in somatotrophs by binding its GHS-R1a receptor and also many effects of ghrelin are mediated via the activation of its receptor. Ghrelin participates in modulation of feeding behaviour by acting on hypothalamic arcuate nucleus. Circulating ghrelin levels increase preprandially and decrease after meals. Ghrelin is an only orexigenic hormone which counteracts to leptin. Non-acylated form of ghrelin has also been suggested to have some biological activities such as cell proliferation, lipolysis, adipogenesis and cardiovascular functions. However the binding receptor of non-acylated ghrelin and its biological functions are still unclear. Circulating ghrelin levels are reported to be increased or decreased in response to physiological and pathological alterations. Ghrelin concentrations are shown to decrease in obese subjects and in patients with type 2 diabetes. It is secreted in circadian rhythm showing especially a nocturnal peak at 2 a.m. It is expected that numerous unknown biological functions of ghrelin, particularly those of non-acylated form, will be elucidated by further studies in the near future.

PDF

___

1) 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. 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: 4753-4758.
2) Asakawa A, Inui A, Kaga T, Katsuura G, Fujimiya M, Fujino MA, Kasuga M, Antagonism of ghrelin receptor reduces food intake and body weight gain in mice. Gut 2003; 52: 947-952.
3) Baldanzi G, Filigheddu N, Cutrupi S, Catapano F, Bonissoni S, Fubini A, Malan D, Baj G, Granata R, Broglio F, Papotti M, Surico N, Bussolino F, Isgaard J, Deghenghi R, Sinigaglia F, Prat M, Muccioli G, Ghigo E, Graziani A. 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; 159:1029-1037.
4) 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: 2180–2184.
5) Bedendi I, Alloatti G, Marcantoni A, Malan D, Catapano F, Ghe C, Deghenghi R, Ghigo E, Muccioli G. Cardiac effects of ghrelin and its endogenous derivatives des-octanoyl ghrelin and des-Gln14-ghrelin. Eur J Pharmacol 2003; 22: 476: 87-95.
6) Bellone S, Rapa A, Vivenza D, Castellino N, Petri A, Bellone J, Me E, Broglio F, Prodam F, Ghigo E, Bona G. Circulating ghrelin levels as function of gender, pubertal status and adiposity in childhood. J Endocrinol Invest 2002; 25: 13-15.
7) Broglio F, Arvat E, Benso A, Gottero C, Muccioli G, Papotti M, 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.
8) Broglio F, Benso A, Gottero C, Prodam F, Gauna C, Filtri L, Arvat E, van der Lely AJ, Deghenghi R, Ghigo E. Non-acylated ghrelin does not possess the pituitaric and pancreatic endocrine activity of acylated ghrelin in humans. J Endocrinol Invest 2003; 26: 192-196.
9) Broglio F, Gottero C, Prodam F, Gauna C, Muccioli G, Papotti M, Abribat T, Van Der Lely AJ, Ghigo E. Non-acylated ghrelin counteracts the metabolic but not the neuroendocrine response to acylated ghrelin in humans. J Clin Endocrinol Metab 2004; 89: 3062-3065.
10) Cappiello V, Ronchi C, Morpurgo PS, Epaminonda P, Arosio M, Beck-Peccoz P, Spada A. Circulating ghrelin levels in basal conditions and during glucose tolerance test in acromegalic patients. Eur J Endocrinol 2002; 147: 189–194.
11) Cassoni P, Papotti M, Ghe C, Catapano F, Sapino A, Graziani A, Deghenghi R, Reissmann T, Ghigo E, Muccioli G. 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 2001; 86:1738-1745.
12) Cassoni P, Ghe C, Marrocco T, Tarabra E, Allia E, Catapano F, Deghenghi R, Ghigo E, Papotti M, Muccioli G. Expression of ghrelin and biological activity of specific receptors for ghrelin and des-acyl ghrelin in human prostate neoplasms and related cell lines. Eur J Endocrinol 2004; 150:173-184.
13) Chanoine JP, Wong AC. Ghrelin gene expression is markedly higher in fetal pancreas compared with fetal stomach: effect of maternal fasting. Endocrinology 2004; 145:3813- 3820.
14) 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: 2791–2798,.
15) Cortelazzi D, Cappiello V, Morpurgo PS, Ronzoni S, Nobile De Santis MS, Cetin I, Beck-Peccoz P, Spada A. Circulating levels of ghrelin in human fetuses. Eur J Endocrinol 2003; 149:111-116.
16) 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: 1714-1719.
17) Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, Purnell JQ. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 2002; 346: 1623–1630.
18) Dall R, Kanaley J, Hansen TK, Moller N, Christiansen JS, Hosoda H, Kangawa K, Jorgensen JO. Plasma ghrelin levels during exercise in healthy subjects and in growth hormonedeficient patients. Eur J Endocrinol 2002; 147: 65-70.
19) 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.
20) Date Y, Nakazato M, Murakami N, Kojima M, Kangawa K, Matsukura S. Ghrelin acts in the central nervous system to stimulate gastric acid secretion. Biochem Biophys Res Commun 2001; 280: 904-907.
21) Date Y, Nakazato M, Hashiguchi S, Dezaki K, Mondal MS, Hosoda H, Kojima M, Kangawa K, Arima T, Matsuo H, Yada T. Ghrelin is present in pancreatic alpha-cells of humans and rats and stimulates insulin secretion. Diabetes 2002; 51:124-129.
22) Dixit VD, Schaffer EM, Pyle RS, Collins GD, Sakthivel SK, Palaniappan R, Lillard JW, Taub DD. Ghrelin inhibits leptinand activation-induced proinflammatory cytokine expression by human monocytes and T cells. J Clin Invest 2004; 114: 57-66.
23) Dornonville De La Cour C, Lindstrom E, Norlen P, Hakanson R. Ghrelin stimulates gastric emptying but is without effect on acid secretion and gastric endocrine cells. Regul Pept 2004; 120: 23-32.
24) Druce M, Bloom SR. Central regulators of food intake. Curr Opin Clin Nutr Metab Care 2003; 6: 361-367.
25) Dzaja A, Dalal MA, Himmerich H, Uhr M, Pollmacher T, Schuld A. Sleep enhances nocturnal plasma ghrelin levels in healthy subjects. Am J Physiol Endocrinol Metab 2004; 286: 963-967.
26) Eden-Engstrom 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) Erdmann J, Lippl F, Schusdziarra V. Differential effect of protein and fat on plasma ghrelin levels in man. Regul Pept 2003; 116: 101-107.
28) Freda PU, Reyes CM, Conwell IM, Sundeen RE, Wardlaw SL. Serum ghrelin levels in acromegaly: effects of surgical and long-acting octreotide therapy. J Clin Endocrinol Metab 2003; 88: 2037-2044.
29) Gauna C, Meyler FM, Janssen JAMJL, Delhanty PJD, Abribat T, van Koetsveld P, Hofland LJ, Broglio F, Ghigo E, van der Lely AJ. Administration of Acylated Ghrelin Reduces Insulin Sensitivity, Whereas the Combination of Acylated Plus Unacylated Ghrelin Strongly Improves Insulin Sensitivity. J Clin Endocrinol Metab 2004; 89: 5035-5042.
30) 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: 2988-2991.
31) Grube D, Forssmann WG. Morphology and function of the entero-endocrine cells. Horm Metab Res 1979; 11: 589-606.
32) Gualillo O, Caminos JE, Kojima M, Kangawa K, Arvat E, Ghigo E, Casanueva FF, Dieguez C. Gender and gonadal influences on ghrelin mRNA levels in rat stomach. Eur J Endocrinol 2001; 144: 687-690.
33) Halem HA, Taylor JE, Dong JZ, Shen Y, Datta R, Abizaid A, Diano S, Horvath T, Zizzari P, Bluet-Pajot MT, Epelbaum J, Culler MD. Novel analogs of ghrelin: physiological and clinical implications. Eur J Endocrinol 2004; 151: 71-75.
34) Hataya Y, Akamizu T, Takaya K, Kanamoto N, Ariyasu H, Saijo M, Moriyama K, Shimatsu A, Kojima M, Kangawa K, Nakao K. A low dose of ghrelin stimulates growth hormone (GH) release synergistically with GH-releasing hormone in humans. J Clin Endocrinol Metab 2001; 86:552-4555.
35) Hosoda H, Kojima M, Matsuo H, Kangawa K. Ghrelin and des-acyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue. Biochem Biophys Res Commun 2000; 279: 909-913.
36) 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: 21995-22000.
37) Hosoda H, Kojima M, Mizushima T, Shimizu S, Kangawa K. Structural divergence of human ghrelin. Identification of multiple ghrelin-derived molecules produced by posttranslational processing. J Biol Chem 2003; 278: 64-70.
38) Hosoda H, Doi K, Nagaya N, Okumura H, Nakagawa E, Enomoto M, Ono F, Kangawa K. Optimum collection and storage conditions for ghrelin measurements: octanoyl modification of ghrelin is rapidly hydrolyzed to desacyl ghrelin in blood samples. Clin Chem 2004; 50: 1077-1080.
39) Ikezaki A, Hosoda H, Ito K, Iwama S, Miura N, Matsuoka H, Kondo C, Kojima M, Kangawa K, Sugihara S. Fasting plasma ghrelin levels are negatively correlated with insulin resistance and PAI-1, but not with leptin, in obese children and adolescents. Diabetes 2002; 51: 3408-3411.
40) Janssen JA, Der Toorn FM, Hofland LJ, van Koetsveld P, Broglio F, Ghigo E, Lamberts SW, Jan VDL. 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.
41) Kangawa K, Matsuo H. Purification and complete amino acid sequence of alpha-human atrial natriuretic polypeptide (alpha-hANP). Biochem Biophys Res Commun 1984; 118: 131-139.
42) Kato M, Sakuma Y. The effect of GHRP-6 on the intracellular Na+ concentration of rat pituitary cells in primary culture. J Neuroendocrinol 1999; 11: 795-800.
43) Katugampola SD, Kuc RE, Maguire JJ, Davenport AP. Gprotein- coupled receptors in human atherosclerosis: comparison of vasoconstrictors (endothelin and thromboxane) with recently de- orphanized (urotensin-II, apelin and ghrelin) receptors. Clin Sci 2002; 103: 171-175.
44) 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.
45) Kitamura S, Yokota I, Hosoda H, Kotani Y, Matsuda J, Naito E, Ito M, Kangawa K, Kuroda Y. Ghrelin concentration in cord and neonatal blood: Relation to fetal growth and energy balance. J Clin Endocrinol Metab 2003; 88: 5473- 5477.
46) 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.
47) Korbonits M, Ciccarelli E, Ghigo E, Grossman AB. The growth hormone secretagogue receptor. Growth Horm 1999; 9: 93-99.
48) 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.
49) Korbonits M, Goldstone AP, Gueorguiev M, Grossman AB. Ghrelin—a hormone with multiple functions. Frontiers in Neuroendocrinology 2004; 25: 27-68.
50) Makino Y, Hosoda H, Shibata K, Makino I, Kojima M, Kangawa K, Kawarabayashi T. Alteration of plasma ghrelin levels associated with the blood pressure in pregnancy. Hypertension 2002; 39: 781-784.
51) Marchesini G, Pagotto U, Bugianesi E, De Iasio R, Manini R, Vanni E, Pasquali R, Melchionda N, Rizzetto M. Low ghrelin concentrations in nonalcoholic fatty liver disease are related to insulin resistance. J Clin Endocrinol Metab 2003; 88:5674-5679.
52) Masaoka T, Suzuki H, Hosoda H, Ota T, Minegishi Y, Nagata H, Kangawa K, Ishii H. Enhanced plasma ghrelin levels in rats with streptozotocin-induced diabetes. FEBS Lett 2003; 541: 64-68.
53) McKee KK, Tan CP, Palyha OC, Liu J, Feighner SD, Hreniuk DL, Smith RG, Howard AD, Van der Ploeg LH. Cloning and characterization of two human G protein-coupled receptor genes (GPR38 and GPR39) related to the growth hormone secretagogue and neurotensin receptors. Genomics 1997; 46:426-434.
54) Miraglia del Giudice E, Santoro N, Cirillo G, Raimondo P, Grandone A, D'Aniello A, Di Nardo M, Perrone L. Molecular screening of the ghrelin gene in Italian obese children: the Leu72Met variant is associated with an earlier onset of obesity. Int J Obes Relat Metab Disord 2004; 28: 447-450.
55) Morton GJ, Schwartz MW. The NPY/AgRP neuron and energy homeostasis. Int J Obesity Relat Metab Disord 2001; 25: 56-62.
56) Muccioli G, Pons N, Ghe C, Catapano F, Granata R, Ghigo E. Ghrelin and des-acyl ghrelin both inhibit isoproterenol-induced lipolysis in rat adipocytes via a non-type 1a growth hormone secretagogue receptor. Eur J Pharmacol 2004; 498: 27-35.
57) Muller AF, Janssen JA, Hofland LJ, Lamberts SW, Bidlingmaier M, Strasburger CJ, Der Lely AJA. 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.
58) Murdolo G, Lucidi P, Di Loreto C, Parlanti N, De Cicco A, Fanelli C, Perriello G, Mughetti D, Pippi R, Brozzetti A, Santeusanio F, De Feo P. Circulating ghrelin levels of visceral obese men are not modified by a short-term treatment with very low doses of GH replacement. J Endocrinol Invest 2003; 26: 244-249.
59) Nagaya N, Uematsu M, Kojima M, Date Y, Nakazato M, Okumura H, Hosoda H, Shimizu W, Yamagishi M, Oya H, Koh H, Yutani C, Kangawa K. Elevated circulating level of ghrelin in cachexia associated with chronic heart failure: relationships between ghrelin and anabolic/catabolic factors. Circulation 2001; 104: 2034-2038.
60) Ott V, Fasshauer M, Dalski A, Meier B, Perwitz N, Klein HH, Tschop M, Klein J. Direct peripheral effects of ghrelin include suppression of adiponectin expression. Horm Metab Res 2002; 34: 640-645.
61) Otto B, Cuntz U, Fruehauf E, Wawarta R, Folwaczny C, Riepl RL, Heiman ML, Lehnert P, Fichter M, Tschöp M. Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa. Eur J Endocrinol 2001; 145: 669-673.
62) Pagotto U, Gambineri A, Vicennati V, Heiman ML, Tschöp M, Pasquali R. Plasma ghrelin, obesity, and the polycystic ovary syndrome: correlation with insulin resistance and androgen levels. J Clin Endocrinol Metab 2002; 87: 5625-5629.
63) Papotti M, Ghe C, Volante M, Muccioli G. Ghrelin and tumors. In: Ghrelin (More Than Simply a Natural GH Secretagogue and/or on Orexigenic Factor) (ed. E. Ghigo), Kluwer Academic, Boston, 2004; 143-164.
64) Pemberton C, Wimalasena P, Yandle T, Soule S, Richards M. C-terminal pro-ghrelin peptides are present in the human circulation. Biochem Biophys Res Commun 2003; 310: 567- 573.
65) Pettersson I, Muccioli G, Granata R, Deghenghi R, Ghigo E, Ohlsson C, Isgaard J. Natural (ghrelin) and synthetic (hexarelin) GH secretagogues stimulate H9c2 cardiomyocyte cell proliferation. J Endocrinol 2002; 175: 201-209.
66) Pong SS, Chaung LY, Dean DC, Nargund RP, Patchett AA, Smith RG. Identification of a new G-protein-linked receptor for growth hormone secretagogues. Mol Endocrinol 1996; 10: 57-61.
67) Poykko S, Ukkola O, Kauma H, Savolainen MJ, Kesaniemi YA. Ghrelin Arg51Gln mutation is a risk factor for type 2 diabetes and hypertension in a random sample of middle-aged subjects. Diabetologia 2003; 46: 455-458.
68) Pöykkö SM, Kellokoski E, Horkko S, Kauma H, Kesaniemi YA, Ukkola O. Low plasma ghrelin is associated with insulin resistance, hypertension, and the prevalence of type 2 diabetes. Diabetes 2003; 52: 2546-2553.
69) Purnell JQ, Weigle DS, Breen PA,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.
70) 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.
71) Ruter J, Kobelt P, Tebbe JJ, Avsar Y, Veh R, Wang L, Klapp BF, Wiedenmann B, Tache Y, Monnikes H. Intraperitoneal injection of ghrelin induces Fos expression in the paraventricular nucleus of the hypothalamus in rats. Brain Res 2003; 991: 26-33.
72) Shiiya T, Nakazato M, Mizuta M, Date Y, Mondal MS, Tanaka M, Nozoe S, Hosoda H, Kangawa K, Matsukura S. Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion. J Clin Endocrinol Metab 2002; 87: 240-244.
73) Smith RG, LHT, Van der Ploeg AD. H, Feighner SD, Cheng K, Hickey GJ, Wyvratt MJ, Fisher Jr, MH., Nargund RP, Patchett AA. Peptidomimetic regulation of growth hormone secretion. Endocr Rev 1997; 18: 621-645.
74) 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.
75) Thompson NM, Gill DA, Davies R, Loveridge N, Houston PA, Robinson IC, Wells T. Ghrelin and des-octanoyl ghrelin promote adipogenesis directly in vivo by a mechanism independent of the type 1a growth hormone secretagogue receptor. Endocrinology 2004; 145:234-242.
76) Tschöp M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature 2000; 407: 908-913.
77) Tschöp M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E, Heiman ML, Circulating ghrelin levels are decreased in human obesity. Diabetes 2001; 50: 707–709.
78) van der Lely AJ, Tschop M, Heiman ML, Ghigo E. Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr Rev 2004; 25: 426-457.
79) 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.
80) Weikel JC, Wichniak A, Ising M, Brunner H, Friess E, Held K, Mathias S, Schmid DA, Uhr M, Steiger A. Ghrelin promotes slow-wave sleep in man. Am J Physiol Endocrinol Metab 2002; 284: 407-415.
81) Wierup N, Svensson H, Mulder H, Sundler F. The ghrelin cell: A novel developmentally regulated islet cell in the human pancreas. Regul Pept 2002; 107:63-69.
82) Wisse BE, Frayo RS, Schwartz MW, Cummings DE. Reversal of cancer anorexia by blockade of central melanocortin receptors in rats. Endocrinology 2001; 142: 3292-3301.