The role of ghrelin in energy homeostasis and its potential clinical relevance (Review)

International Journal of Molecular Medicine

Volumn 26, Issue 6, 2010, Pages 771-778

  Cheng, Kai Chun ^a   Li, Ying Xiao ^a   Asakawa, Akihiro ^a   Inui, Akio ^a  

^a KAGOSHIMA UNIVERSITY   (Japan)

Author keywords

Clinical application; Energy balance; Ghrelin; Gut motility

Indexed keywords

ACYL GHRELIN; CAPSAICIN; CISPLATIN; CYTOTOXIC AGENT; DIGESTIVE TRACT AGENT; GHRELIN; GHRELIN AGONIST; GHRELIN ANTAGONIST; GHRELIN RECEPTOR; GLUCOSE; GROWTH HORMONE SECRETAGOGUE; GROWTH HORMONE SECRETAGOGUE RECEPTOR; HORMONE RECEPTOR BLOCKING AGENT; HORMONE RECEPTOR STIMULATING AGENT; INSULIN; NITRIC OXIDE; NITROFEN; OBESTATIN; ONDANSETRON; UNCLASSIFIED DRUG;

AGING; ANOREXIA; ANOREXIA NERVOSA; APPETITE; ATHEROSCLEROSIS; BRAIN; BULIMIA; CACHEXIA; CARDIOVASCULAR DISEASE; CARDIOVASCULAR EFFECT; CHEMOTHERAPY INDUCED EMESIS; CONGENITAL DIAPHRAGM HERNIA; CONGESTIVE CARDIOMYOPATHY; CONGESTIVE HEART FAILURE; DELAYED GASTRIC EMPTYING; DRUG MECHANISM; DYSPEPSIA; EARLY SATIETY; EATING DISORDER; ENERGY BALANCE; EXON; FOOD INTAKE; GASTROINTESTINAL MOTILITY; GLUCOSE BLOOD LEVEL; GLUCOSE METABOLISM; GROWTH HORMONE DEFICIENCY; HOMEOSTASIS; HORMONE BLOOD LEVEL; HORMONE SYNTHESIS; HUMAN; HYPERGLYCEMIA; HYPOPITUITARISM; ILEUS; IMMUNOMODULATION; IN VITRO STUDY; IN VIVO STUDY; INSULIN RELEASE; INSULIN RESISTANCE; INTRON; LUNG DEVELOPMENT; LUNG HYPOPLASIA; METABOLIC BONE DISEASE; NAUSEA; NEOPLASM; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; OSTEOPOROSIS; POSTOPERATIVE ILEUS; PRADER WILLI SYNDROME; PRIORITY JOURNAL; PROTEIN FUNCTION; REVIEW; STOMACH; STOMACH ACID SECRETION; STOMACH DISEASE; STOMACH EMPTYING; STOMACH PARESIS; T LYMPHOCYTE;

ANIMALS; GHRELIN; HOMEOSTASIS; HUMANS;

EID: 78649976872     PISSN: 11073756     EISSN: 1791244X     Source Type: Journal    
DOI: 10.3892/ijmm-00000524     Document Type: Review

References (94)

1. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H and Kangawa K: Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402: 656-660, 1999.
2. Hosoda H, Kojima M, Mizushima T, Shimizu S and Kangawa K: Structural divergence of human ghrelin. Identification of multiple ghrelin-derived molecules produced by post-translational processing. J Biol Chem 278: 64-70, 2003. (Pubitemid 36043544)
3. Bowers CY, Momany F, Reynolds GA, Chang D, Hong A and Chang K: Structure-activity relationships of a synthetic pentapeptide that specifically releases growth hormone in vitro. Endocrinology 106: 663-667, 1980. (Pubitemid 10135092)
4. Bowers CY, Momany FA, Reynolds GA and Hong A: On the in vitro and in vivo activity of a new synthetic hexapeptide that acts on the pituitary to specifically release growth hormone. Endocrinology 114: 1537-1545, 1984.
5. Bowers CY: Unnatural growth hormone-releasing peptide begets natural ghrelin. J Clin Endocrinol Metab 86: 1464-1469, 2001.
6. Korbonits M, Goldstone AP, Gueorguiev M and Grossman AB: Ghrelin-A hormone with multiple functions. Front Neuroendocrinol 25: 27-68, 2004.
7. Howard AD, Feighner SD, Cully DF, et al: A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 273: 974-977, 1996.
8. Kojima M: The discovery of ghrelin - a personal memory. Regul Pept 145: 2-6, 2008.
9. Tanaka M, Hayashida Y, Iguchi T, Nakao N, Nakai N and Nakashima K: Organization of the mouse ghrelin gene and promoter: occurrence of a short noncoding first exon. Endocrinology 142: 3697-3700, 2001. (Pubitemid 32681782)
10. Hosoda H, Kojima M and Matsuo H: Purification and characterization of rat des-Gln14-Ghrelin, a second endogenous ligand for the growth hormone secretagogue receptor. J Biol Chem 275: 21995-22000, 2000. (Pubitemid 30621774)
11. Bednarek MA, Feighner SD, Pong SS, et al: Structure-function studies on the new growth hormone-releasing peptide, ghrelin: minimal sequence of ghrelin necessary for activation of growth hormone secretagogue receptor 1a. J Med Chem 43: 4370-4376, 2000.
12. 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 141: 4255-4261, 2000.
13. Kojima M, Hosoda H and Kangawa K: Purification and distribution of ghrelin: the natural endogenous ligand for the growth hormone secretagogue receptor. Horm Res 56: 93-97, 2001. (Pubitemid 34062902)
14. Dass NB, Munonyara M, Bassil AK, et al: Growth hormone secretagogue receptors in rat and human gastrointestinal tract and the effects of ghrelin. Neuroscience 120: 443-453, 2003. (Pubitemid 37288779)
15. Andrews PL and Sanger GJ: Abdominal vagal afferent neurones: an important target for the treatment of gastrointestinal dysfunction. Curr Opin Pharmacol 2: 650-656, 2002.
16. Bedendi I, Alloatti G, Marcantoni A, et al: Cardiac effects of ghrelin and its endogenous derivatives des-octanoyl ghrelin and des-Gln14-ghrelin. Eur J Pharmacol 476: 87-95, 2003.
17. Zhang JV, Ren PG, Avsian-Kretchmer O, Luo CW, Rauch R, Klein C and Hsueh AJ: Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake. Science 310: 996-999, 2005.
18. Qi X, Li L, Yang G, et al: Circulating obestatin levels in normal subjects and in patients with impaired glucose regulation and type 2 diabetes mellitus. Clin Endocrinol 66: 593-597, 2007.
19. Nakahara T, Harada T, Yasuhara D, et al: Plasma obestatin concentrations are negatively correlated with body mass index, insulin resistance index, and plasma leptin concentrations in obesity and anorexia nervosa. Biol Psychiatry 64: 252-255, 2008. (Pubitemid 351927261)
20. Guan XM, Yu H, Palyha OC, et al: Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Brain Res Mol Brain Res 48: 23-29, 1997. (Pubitemid 27298124)
21. Willesen MG, Kristensen P and Rømer J: Co-localization of growth hormone secretagogue receptor and NPY mRNA in the arcuate nucleus of the rat. Neuroendocrinology 70: 306-316, 1999.
22. Batterham RL, Cowley MA, Small CJ, et al: Gut hormone PYY(3-36) physiologically inhibits food intake. Nature 418: 650-654, 2002.
23. Schwartz MW, Woods SC, Porte D Jr, Seeley RJ and Baskin DG: Central nervous system control of food intake. Nature 404: 661-671, 2000. (Pubitemid 30205071)
24. Date Y, Murakami N, Toshinai K, et al: The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats. Gastroenterology 123: 1120-1128, 2002.
25. Cummings DE and Foster KE: Ghrelin-leptin tango in bodyweight regulation. Gastroenterology 124: 1532-1535, 2003.
26. Fujimiya M, Asakawa A, Ataka K, Kato I and Inui A: Different effects of ghrelin, des-acyl ghrelin and obestatin on gastroduodenal motility in conscious rats. World J Gastroenterol 14: 6318-6326, 2008.
27. Carreira MC, Camina JP, Smith RG and Casanueva FF: Agonist-specific coupling of growth hormone secretagogue receptor type 1a to different intracellular signaling systems. Role of adenosine. Neuroendocrinology 79: 13-25, 2004.
28. Wren AM, Small CJ, Abbott CR, et al: Ghrelin causes hyperphagia and obesity in rats. Diabetes 50: 2540-2547, 2001.
29. Tschöp M, Smiley DL and Heiman ML: Ghrelin induces adiposity in rodents. Nature 407: 908-913, 2000.
30. Cummings DE, Foster-Schubert KE and Overduin J: Ghrelin and energy balance: focus on current controversies. Curr Drug Targets 6: 153-169, 2005.
31. Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE and Weigle DS: A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 50: 1714-1719, 2001.
32. Natalucci G, Riedl S, Gleiss A, Zidek T and Frisch H: Spontaneous 24-h ghrelin secretion pattern in fasting subjects: maintenance of a meal-related pattern. Eur J Endocrinol 152: 845-850, 2005.
33. Cummings DE, Frayo RS, Marmonier C, Aubert R and Chapelot D: Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily without time- and food-related cues. Am J Physiol Endocrinol Metab 287: 297-304, 2004. (Pubitemid 38943896)
34. Pusztai P, Sarman B, Ruzicska E, Toke J, Racz K, Somogyi A and Tulassay Z: Ghrelin: a new peptide regulating the neurohormonal system, energy homeostasis and glucose metabolism. Diabetes Metab Res Rev 24: 343-352, 2008.
35. Otto B, Cuntz U, Fruehauf E, et al: Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa. Eur J Endocrinol 145: 669-673, 2001.
36. Otto B, Tschöp M, Frühauf E, Heldwein W, Fichter M, Otto C and Cuntz U: Postprandial ghrelin release in anorectic patients before and after weight gain. Psychoneuroendocrinology 30: 577-581, 2005. (Pubitemid 40461792)
37. Murata M, Okimura Y, Iida K, et al: Ghrelin modulates the downstream molecules of insulin-signaling in hepatoma cells. J Biol Chem 227: 5667-5674, 2002.
38. Broglio F, Arvat E, Benso A, et al: Ghrelin, anatural GH secretagogue produced by the stomach, induces hyperglycemia and reduces insulin secretion in humans. J Clin Endocrinol Metab 86: 5083-5086, 2001.
39. Svensson J, Lönn L, Jansson JO, et al: Two-month treatment of obese subjects with the oral growth hormone (GH) secretagogue MK-677 increases GH secretion, fat-free mass, and energy expenditure. J Clin Endocrinol Metab 83: 363-369, 1998. (Pubitemid 28496507)
40. Gauna C, Meyler FM, Janssen JA, et al: Administration of acylated ghrelin reduces insulin sensitivity, whereas the combination of acylated plus unacylated ghrelin strongly improves insulin sensitivity. J Clin Endocrinol Metab 89: 5035-5042, 2004. (Pubitemid 39391445)
41. Van der Lely AJ, Tschöp M, Heiman ML and Ghigo E: Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr Rev 25: 426-457, 2004.
42. Koo GC, Huang C, Camacho R, et al: Immune enhancing effect of a growth hormone secretagogue. J Immunol 166: 4195-4201, 2001.
43. Basa NR, Wang L, Arteaga JR, Heber D, Livingston EH and Tache Y: Bacterial lipopolysaccharide shifts fasted plasma ghrelin to postprandial levels in rats. Neurosci Lett 343: 25-28, 2003.
44. Wu R, Zhou M, Cui X, Simms HH and Wang P: Upregulation of cardiovascular ghrelin receptor occurs in the hyperdynamic phase of sepsis. Am J Physiol Heart Circ Physiol 287: 1296-1302, 2004.
45. Smith RG, Jiang H and Sun Y: Developments in ghrelin biology and potential clinical relevance. Trends Endocrinol Metab 16: 436-442, 2005. (Pubitemid 41506951)
46. Dixit VD, Schaffer EM, Pyle RS, et al: Ghrelin inhibits leptinand activation-induced proinflammatory cytokine expression by human monocytes and T cells. J Clin Invest 114: 57-66, 2004.
47. Masuda Y, Tanaka T, Inomata N, et al: Ghrelin stimulates gastric acid secretion and motility in rats. Biochem Biophys Res Commun 276: 905-908, 2000.
48. Sibilia V, Pagani F, Guidobono F, Locatelli V, Torsello A, Deghenghi R and Netti C: Evidence for a central inhibitory role of growth hormone secretagogues and ghrelin on gastric acid secretion in conscious rats. Neuroendocrinology 75: 92-97, 2002. (Pubitemid 34195769)
49. Brzozowski T, Konturek PC, Drozdowicz D, et al: Role of central and peripheral ghrelin in the mechanism of gastric mucosal defence. Inflammopharmacology 13: 45-62, 2005. (Pubitemid 41607368)
50. Zheng J, Ariga H, Taniguchi H, Ludwig K and Takahashi T: Ghrelin regulates gastric phase III-like contractions in freely moving conscious mice. Neurogastroenterol Motil 21: 78-84, 2008.
51. Fujino K, Inui A, Asakawa A, Kihara N, Fujimura M and Fujimiya M: Ghrelin induces fasted motor activity of the gastrointestinal tract in conscious fed rats. J Physiol 550: 227-240, 2003. (Pubitemid 36869283)
52. Tack J, Depoortere I, Bisschops R, et al: Influence of ghrelin on interdigestive gastrointestinal motility in humans. Gut 55: 327-333, 2006.
53. Trudel L, Bouin M, Tomasetto C, et al: Two new peptides to improve post-operative gastric ileus in dog. Peptides 24: 531-534, 2003. (Pubitemid 36829341)
54. Trudel L, Tomasetto C, Rio MC, Bouin M, Plourde V, Eberling P and Poitras P: Ghrelin/motilin-related peptide is a potent prokinetic to reverse gastric postoperative ileus in rat. Am J Physiol Gastrointest Liver Physiol 282: 948-952, 2002.
55. Venkova K and Greenwood-Van Meerveld B: Application of ghrelin to gastrointestinal diseases. Curr Opin Investig Drugs 9: 1103-1107, 2008.
56. Chen CY, Inui A, Asakawa A, et al: Des-acyl ghrelin acts by CRF type 2 receptors to disrupt fasted stomach motility in conscious rats. Gastroenterology 129: 8-25, 2005.
57. Ataka K, Inui A, Asakawa A, Kato I and Fujimiya M: Obestatin inhibits motor activity in the antrum and duodenum in the fed state of conscious rats. Am J Physiol Gastrointest Liver Physiol 294: 1210-1218, 2008.
58. De Smet B, Thijs T, Peeters TL and Depoortere I: Effect of peripheral obestatin on gastric emptying and intestinal contractility in rodents. Neurogastroenterol Motil 19: 211-217, 2007.
59. Gourcerol G, Coskun T, Craft LS, et al: Preproghrelin-derived peptide, obestatin, fails to influence food intake in lean or obese rodents. Obesity 15: 2643-2652, 2007.
60. Bassil AK, Häglund Y, Brown J, et al: Little or no ability of obestatin to interact with ghrelin or modify motility in the rat gastrointestinal tract. Br J Pharmacol 150: 58-64, 2007.
61. Volante M, Fulcheri E, Allìa E, Cerrato M, Pucci A and Papotti M: Ghrelin expression in fetal, infant, and adult human lung. J Histochem Cytochem 50: 1013-1021, 2002.
62. Correia-Pinto J, Baptista MJ, Pedrosa C, Estevão-Costa J, Flake AW and Leite-Moreira AF: Fetal heart development in the nitrofen-induced CDH rat model: the role of mechanical and nonmechanical factors. J Pediatr Surg 38: 1444-1451, 2003.
63. 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 59: 531-537, 2006.
64. 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 280: 1483-1487, 2001.
65. Baldanzi G, Filigheddu N, Cutrupi S, 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 159: 1029-1037, 2002.
66. Dieguez C and Casanueva FF: Influence of metabolic substrates and obesity on growth hormone secretion. Trends Endocrinol Metab 6: 55-59, 1995.
67. Tschöp M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E and Heiman ML: Circulating ghrelin levels are decreased in human obesity. Diabetes 50: 707-709, 2001. (Pubitemid 32242624)
68. Ikezaki A, Hosoda H, Ito K, et al: Fasting plasma ghrelin levels are negatively correlated with insulin resistance and PAI-1, but not with leptin, in obese children and adolescents. Diabetes 51: 3408-3411, 2002. (Pubitemid 35403443)
69. Hansen TK, Dall R, Hosoda H, Kojima M, Kangawa K, Christiansen JS and Jorgensen JO: Weight loss increases circulating levels of ghrelin in human obesity. Clin Endocrinol 56: 203-206, 2002. (Pubitemid 34233957)
70. Levin BE and Keesey RE: Defense of differing body weight set points in diet-induced obese and resistant rats. Am J Physiol 274: 412-419, 1998.
71. Levin BE: Arcuate NPY neurons and energy homeostasis in diet-induced obese and resistant rats. Am J Physiol 276: 382-387, 1999.
72. English PJ, Ghatei MA, Malik IA, Bloom SR and Wilding JP: Food fails to suppress ghrelin levels in obese humans. J Clin Endocrinol Metab 87: 2984, 2002.
73. Inui A: Eating behavior in anorexia nervosa-an excess of both orexigenic and anorexigenic signaling? Mol Psychiatry 6: 620-624, 2001.
74. Shiiya T, Nakazato M, Mizuta M, et al: Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion. J Clin Endocrinol Metab 87: 240-244, 2002. (Pubitemid 34084697)
75. Aggarwal A: Helicobacter pylori infection: a cause of growth delay in children. Indian Pediatr 35: 191-192, 1998.
76. Rigamonti AE, Pincelli AI, Corrà B, et al: Plasma ghrelin concentrations in elderly subjects: comparison with anorexic and obese patients. J Endocrinol 175: 1-5, 2002.
77. Cuntz U, Fruhauf E, Wawarta R, et al: A role for the novel weight-regulating hormone ghrelin in anorexia nervosa. Am Clin Lab 21: 22-23, 2002.
78. Nedvídková J, Krykorková I, Barták V, Papezová H, Gold PW, Alesci S and Pacak K: Loss of meal-induced decrease in plasma ghrelin levels in patients with anorexia nervosa. J Clin Endocrinol Metab 88: 1678-1682, 2003. (Pubitemid 36623387)
79. Kaye WH, Berrettini W, Gwirtsman H and George DT: Altered cerebrospinal fluid neuropeptide Y and peptide YY immunoreactivity in anorexia and bulimia nervosa. Arch Gen Psychiatry 47: 548-556, 1990. (Pubitemid 20189967)
80. Tanaka M, Naruo T, Muranaga T, et al: Increased fasting plasma ghrelin levels in patients with bulimia nervosa. Eur J Endocrinol 146: 1-3, 2001.
81. Colao A, Marzullo P, Di Somma C and Lombardi G: Growth hormone and the heart. Clin Endocrinol 54: 137-154, 2001.
82. Claycomb WC, Lanson NA Jr, Stallworth BS, Egeland DB, Delcarpio JB, Bahinski A and Izzo NJ Jr: HL-1 cells: a cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte. Proc Natl Acad Sci USA 95: 2979-2984, 1998.
83. González-Juanatey JR, Piñeiro R, Iglesias MJ, Gualillo O, Kelly PA, Diéguez C and Lago F: GH prevents apoptosis in cardiomyocytes cultured in vitro through a calcineur-independent mechanism. J Endocrinol 180: 325-335, 2004.
84. Iglesias MJ, Piñeiro R, Blanco M, et al: Growth hormone releasing peptide (ghrelin) is synthesized and secreted by cardiomyocytes. Cardiovasc Res 62: 481-488, 2004.
85. Okumura H, Nagaya N, Enomoto M, Nakagawa E, Oya H and Kangawa K: Vasodilatory effect of ghrelin, an endogenous peptide from the stomach. J Cardiovasc Pharmacol 39: 779-783, 2002.
86. Wiley KE and Davenport AP: Comparison of the effects of atherosclerosis and nitrate therapy on responses to nitric oxide and endothelin-1 in human arteries in vitro. Clin Sci 48: 124-127, 2002.
87. 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 104: 2034-2038, 2001. (Pubitemid 33027043)
88. 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 104: 1430-1435, 2001. (Pubitemid 32880158)
89. Frascarelli S, Ghelardoni S, Ronca-Testoni S and Zucchi R: Effect of ghrelin and synthetic growth hormone secretagogues in normal and ischemic rat heart. Basic Res Cardiol 98: 401-405, 2003.
90. Matsumura K, Tsuchihashi T, Fujii K, Abe I and Iida M: Central ghrelin modulates sympathetic activity in conscious rabbits. Hypertension 40: 694-699, 2002.
91. Liu YL, Malik NM, Sanger GJ and Andrews PL: Ghrelin alleviates cancer chemotherapy-associated dyspepsia in rodents. Cancer Chemother Pharmacol 58: 326-333, 2006.
92. Suzuki H, Nishizawa T and Hibi T: Therapeutic strategies for functional dyspepsia and the introduction of the Rome III classification. J Gastroenterol 41: 513-523, 2006.
93. Tritos NA and Kokkotou EG: The physiology and potential clinical applications of ghrelin, a novel peptide hormone. Mayo Clin Proc 81: 653-660, 2006.
94. Inui A, Asakawa A, Bowers CY, Mantovani G, Laviano A, Meguid MM and Fujimiya M: Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ. FASEB J 18: 439-456, 2004.