Metabolic and cardiovascular effects of ghrelin
https://doi.org/10.14341/2071-8713-5048
Abstract
Ghrelin is an endogenous ligand for growth hormone receptor, which is synthesized as a prohormone, and then proteolytically converted into 28-amino acid peptide. This peptide stimulates the secretion of growth hormone, regulates food intake, effect on carbohydrate and lipid metabolism. Ghrelin enhances the bioavailability of nitric oxide and maintains the balance between endothelin-1 and nitric oxide in the vascular wall. It increases cardiac output, and reduces blood pressure and systemic vascular resistance. Antiinflammatory effect of ghrelin is also appreciated. Since ghrelin is a circulating peptide that stimulates appetite and regulate energy balance, and its role in the development of obesity and type 2 diabetes it is the subject of intense research. A variety of metabolic functions of ghrelin requires extreme caution in the use of therapeutic approaches aimed at the stimulation or blockade of its action.
References
1. Andralojc KM, Mercalli A, Nowak KW, et al. Ghrelin-producing epsilon cells in the developing and adult human pancreas. Diabetologia. 2009;52(3):486-493. [PubMed]
2. Ashby D, Choi P, Bloom S. Gut hormones and the treatment of disease cachexia. Proceedings of the Nutrition Society. 2008;67(3):263-269. [PubMed]
3. Barazzoni R, Zanetti M, Ferreira C, et al. Relationships between desacylated and acylated ghrelin and insulin sensitivity in the metabolic syndrome. Journal of Clinical Endocrinology and Metabolism. 2007;92:3935-3940. [PubMed]
4. Becskei C, Bilik KU, Klussmann S, Jarosch F, Lutz TA, Riediger T. The anti-ghrelin spiegelmer NOX-B11-3 blocks ghrelin- but not fasting-induced neuronal activation in the hypothalamic arcuate nucleus. Journal of Neuroendocrinology. 2008;20(1):85-92. [PubMed]
5. Broglio F, Benso A, Castiglioni C, et al. The endocrine response to ghrelin as a function of gender in humans in young and elderly subjects. Journal of Clinical Endocrinology and Metabolism. 2003;88(4):1537-1542. [PubMed]
6. Broglio F, Gottero C, Prodam F, et al. Ghrelin secretion is inhibited by glucose load and insulin-induced hypoglycaemia but unaffected by glucagon and arginine in humans. Clinical Endocrinology. 2004;61(4):503-509. [PubMed]
7. Broglio F, Prodam F, Riganti F, et al. The continuous infusion of acylated ghrelin enhances growth hormone secretion and worsens glucose metabolism in humans. Journal of Endocrinological Investigation. 2008;31(9):788-794. [PubMed]
8. Cao J-M, Ong H, Chen C. Effects of ghrelin and synthetic GH secretagogues on the cardiovascular system. Trends in Endocrinology and Metabolism. 2006;17(1):13-18. [PubMed]
9. Cassoni P, Papotti M, Ghè C, et al. 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. Journal of Clinical Endocrinology and Metabolism. 2001;86(4):1738-1745. [PubMed]
10. Chen C-Y, Inui A, Asakawa A, et al. Des-acyl ghrelin acts by CRF type 2 receptors to disrupt fasted stomach motility in conscious rats. Gastroenterology. 2005;129(1):8-25. [PubMed]
11. Choi K, Roh S-G, Hong Y-H, et al. The role of ghrelin and growth hormone secretagogues receptor on rat adipogenesis. Endocrinology. 2003;144(3):754-759. [PubMed]
12. Cummings DE, Clement K, Purnell JQ, et al. Elevated plasma ghrelin levels in Prader- Willi syndrome. Nature Medicine. 2002;8(7):643-644.
13. DeBoer MD, Zhu X, Levasseur PR, et al. Ghrelin treatment of chronic kidney disease: improvements in lean body mass and cytokine profile. Endocrinology. 2008;149(2):827- 835. [PMC free article] [PubMed]
14. Dimaraki EV, Jaffe CA. Role of endogenous ghrelin in growth hormone secretion, appetite regulation and metabolism. Reviews in Endocrine and Metabolic Disorders. 2006;7(4):237-249. [PubMed]
15. Dixit VD, Schaffer EM, Pyle RS, et al. Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells. Journal of Clinical Investigation. 2004;114(1):57-66. [PMC free article] [PubMed]
16. English PJ, Ghatei MA, Malik IA, Bloom SR, Wilding JPH. Food fails to suppress ghrelin levels in obese humans. Journal of Clinical Endocrinology and Metabolism. 2002;87(6):2984-2987. [PubMed] 17. Erdmann J, Lippl F, Schusdziarra V. Differential effect of protein and fat on plasma ghrelin levels in man. Regulatory Peptides. 2003;116(1-3):101-107. [PubMed]
17. Franks S. Polycystic ovary syndrome. The New England Journal of Medicine. 1995;333:853-861. [PubMed]
18. Frascarelli S, Ghelardoni S, Ronca-Testoni S, Zucchi R. Effect of ghrelin and synthetic growth hormone secretagogues in normal and ischemic rat heart. Basic Research in Cardiology. 2003;98(6):401-405. [PubMed]
19. García EA, Korbonits M. Ghrelin and cardiovascular health. Current Opinion in Pharmacology. 2006;6(2):142-147. [PubMed]
20. Gauna C, Delhanty PJD, Hofland LJ, et al. Ghrelin stimulates, whereas des-octanoyl ghrelin inhibits, glucose output by primary hepatocytes. Journal of Clinical Endocrinology and Metabolism. 2005;90(2):1055-1060. [PubMed]
21. Ghelardoni S, Carnicelli V, Frascarelli S, Ronca-Testoni S, Zucchi R. Ghrelin tissue distribution: comparison between gene and protein expression. Journal of Endocrinological Investigation. 2006;29(2):115-121. [PubMed]
22. Granado M, Priego T, Martín AI, Villanúa M, López-Calderón A. Anti-inflammatory effect of the ghrelin agonist growth hormone-releasing peptide-2 (GHRP-2) in arthritic rats. American Journal of Physiology. 2005;288(3):E486-E492. [PubMed]
23. Granata R, Settanni F, Biancone L, et al. Acylated and unacylated ghrelin promote proliferation and inhibit apoptosis of pancreatic betacells and human islets: involvement of 3, 5 cyclic adenosine monophosphate/protein kinase A, extracellular signalregulated kinase 1/2, and phosphatidyl inositol 3-kinase/Akt signaling. Endocrinology. 2007;148(2):512-529. [PubMed]
24. Greenman Y, Golani N, Gilad S, Yaron M, Limor R, Stern N. Ghrelin secretion is modulated in a nutrient- and gender-specific manner. Clinical Endocrinology. 2004;60(3):382-388. [PubMed]
25. Gualillo O, Lago F, Gómez-Reino J, Casanueva FF, Dieguez C. Ghrelin, a widespread hormone: insights into molecular and cellular regulation of its expression and mechanism of action. FEBS Letters. 2003;552(2-3):105-109. [PubMed]
26. Hosoda H, Kojima M, Kangawa K. Ghrelin and the regulation of food intake and energy balance. Molecular Interventions. 2002;2(8):494-503. [PubMed]
27. Hye SP, Lee K-U, Young SK, Cheol YP. Relationships between fasting plasma ghrelin levels and metabolic parameters in children and adolescents. Metabolism. 2005;54(7):925-929. [PubMed]
28. Iglesias MJ, Piñeiro R, Blanco M, et al. Growth hormone releasing peptide (ghrelin) is synthesized and secreted by cardiomyocytes. Cardiovascular Research. 2004;62(3):481-488. [PubMed]
29. Kissebah AH, Sonnenberg GE, Myklebust J, et al. Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome. Proceedings of the National Academy of Sciences of the United States of America. 2000;97(26):14478-14483. [PMC free article] [PubMed]
30. Kleinz MJ, Maguire JJ, Skepper JN, [125I-His9]-ghrelin, a novel radioligand for localizing GHS orphan receptors in human and rat tissue; up-regulation of receptors with atherosclerosis. British Journal of Pharmacology. 2001;134(1):143-149. [PMC free article] [PubMed] 32. Kleinz MJ, Maguire JJ, Skepper JN, Davenport AP. Functional and immunocytochemical evidence for a role of ghrelin and des-octanoyl ghrelin in the regulation of vascular tone in man. Cardiovascular Research. 2006;69(1):227-235. [PubMed]
31. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growthhormone- releasing acylated peptide from stomach. Nature. 1999;402(6762):656-660. [PubMed]
32. Kojima M, Hosoda H, Matsuo H, Kangawa K. Ghrelin: discovery of the natural endogenous ligand for the growth hormone secretagogue receptor. Trends in Endocrinology and Metabolism. 2001;12(3):118-122. [PubMed]
33. Kola B, Grossman A, Korbonits M. The role of AMP-activated protein kinase in obesity. Frontiers of Hormone Research. 2008;36:198-211. [PubMed]
34. Kola B, Hubina E, Tucci SA, et al. Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase. Journal of Biological Chemistry. 2005;280(26):25196-25201. [PubMed]
35. Langenberg C, Bergstrom J, Laughlin GA, Barrett-Connor E. Ghrelin and the metabolic syndrome in older adults. Journal of Clinical Endocrinology and Metabolism. 2005;90(12):6448-6453. [PubMed]
36. Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. Journal of Clinical Endocrinologyand Metabolism. 1999;84(1):165-169. [PubMed]
37. Leite-Moreira AF, Rocha-Sousa A, Henriques-Coelho T. Cardiac, skeletal, and smooth muscle regulation by ghrelin. Vitamins and Hormones. 2007;77:207-238. [PubMed]
38. Li WG, Gavrila D, Liu X, et al. Ghrelin inhibits proinflammatory responses and nuclear factor-B activation in human endothelial cells. Circulation. 2004;109(18):2221-2226. [PubMed]
39. Mano-Otagiri A, Ohata H, Iwasaki-Sekino A, Nemoto T, Shibasaki T. Ghrelin suppresses noradrenaline release in the brown adipose tissue of rats. Journal of Endocrinology. 2009;201(3):341-349. [PubMed]
40. Mizia-Stec K, Zahorska-Markiewicz B, Olszanecka-Glinianowicz M, et al. Ghrelin as a potential blood pressure reducing factor in obese women during weight loss treatment. Endokrynologia Polska. 2008;59(3):207-211. [PubMed]
41. Moulin A, Demange L, Bergé G, et al. Toward potent ghrelin receptor ligands based on trisubstituted 1,2,4-triazole structure. 2. Synthesis and pharmacological in vitro and in vivo evaluations. Journal of Medicinal Chemistry. 2007;50(23):5790-5806. [PubMed]
42. Murata M, Okimura Y, Iida K, et al. Ghrelin modulates the downstream molecules of insulin signaling in hepatoma cells. Journal of Biological Chemistry. 2002;277(7):5667- 5674. [PubMed]
43. Nagaya N, Kojima M, Kangawa K. Ghrelin, a novel growth hormone-releasing peptide, in the treatment of cardiopulmonary-associated cachexia. Internal Medicine. 2006;45(3):127-134. [PubMed]
44. Nagaya N, Moriya J, Yasumura Y, et al. Effects of ghrelin administration on left ventricular function, exercise capacity, and muscle wasting in patients with chronic heart failure. Circulation. 2004;110(24):3674-3679. [PubMed]
45. 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(17):2034-2038. [PubMed]
46. Nakazato M, Murakami N, Date Y, et al. A role for ghrelin in the central regulation of feeding. Nature. 2001;409(6817):194-198. [PubMed]
47. Pagotto U, Gambineri A, Vicennati V, Heiman ML, Tschop M, Pasquali R. Plasma ghrelin, obesity, and the polycystic ovary syndrome: correlation with insulin resistance and androgen levels. Journal of Clinical Endocrinology and Metabolism. 2002;87(12):5625- 5629. [PubMed]
48. Qader SS, Håkanson R, Rehfeld JF, Lundquist I, Salehi A. Proghrelin-derived peptides influence the secretion of insulin, glucagon, pancreatic polypeptide and somatostatin: a study on isolated islets from mouse and rat pancreas. Regulatory Peptides. 2008;146(1-3):230-237. [PubMed]
49. Rabe K, Lehrke M, Parhofer KG, Broedl UC. Adipokines and insulin resistance. Molecular Medicine. 2008;14(11-12):741-751. [PMC free article] [PubMed]
50. Rodríguez A, Gómez-Ambrosi J, Catalán V, et al. Acylated and desacyl ghrelin stimulate lipid accumulation in human visceral adipocytes. International Journal of Obesity. 2009;33(5):541-552. [PubMed]
51. Sakata I, Yang J, Lee CE, et al. Colocalization of ghrelin O-acyltransferase and ghrelin in gastric mucosal cells. American Journal of Physiology. 2009;297(1):E134-E141. [PMC free article] [PubMed]
52. Santosa S, Demonty I, Lichtenstein AH, Cianflone K, Jones PJH. An investigation of hormone and lipid associations after weight loss in women. Journal of the American College of Nutrition. 2007;26(3):250-258. [PubMed]
53. Schellekens H, Dinan TG, Cryan JF. Lean mean fat reducing "ghrelin" machine: hypothalamic ghrelin and ghrelin receptors as therapeutic targets in obesity. Neuropharmacology. 2010;58(1):2-16. [PubMed]
54. Schöfl C, Horn R, Schill T, Schlösser HW, Müller MJ, Brabant G. Circulating ghrelin levels in patients with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism. 2002;87(10):4607-4610. [PubMed]
55. Soeki T, Kishimoto I, Schwenke DO, et al. Ghrelin suppresses cardiac sympathetic activity and prevents early left ventricular remodeling in rats with myocardial infarction. American Journal of Physiology. 2008;294(1):H426-H432. [PubMed]
56. Soriano-Guillén L, Barrios V, Campos-Barros Á, Argente J. Ghrelin levels in obesity and anorexia nervosa: effect of weight reduction or recuperation. Journal of Pediatrics. 2004;144(1):36-42. [PubMed]
57. St-Pierre DH, Karelis AD, Coderre L, et al. Association of acylated and nonacylated ghrelin with insulin sensitivity in overweight and obese postmenopausal women. Journal of Clinical Endocrinology and Metabolism. 2007;92(1):264-269. [PubMed]
58. Tesauro M, Schinzari F, Iantorno M, et al. Ghrelin improves endothelial function in patients with metabolic syndrome. Circulation. 2005;112(19):2986-2992. [PubMed]
59. Tesauro M, Schinzari F, Rovella V, et al. Ghrelin restores the endothelin 1/nitric oxide balance in patients with obesity-related metabolic syndrome. Hypertension. 2009;54(5):995-1000. [PubMed]
60. Thompson NM, Gill DA, Davies R, et al. Ghrelin and desoctanoyl ghrelin promote adipogenesis directly in vivo by a mechanism independent of the type 1a growth hormone secretagogue receptor. Endocrinology. 2004;145:234-242. [PubMed]
61. Toshinai K, Yamaguchi H, Sun Y, et al. Des-acyl ghrelin induces food intake by a mechanism independent of the growth hormone secretagogue receptor. Endocrinology. 2006;147(5):2306-2314. [PubMed] 64. Tschöp M, Wawarta R, Riepl RL, et al. Post-prandial decrease of circulating human ghrelin levels. Journal of Endocrinological Investigation. 2001;24(6):RC19-RC21. [PubMed]
62. Ukkola O. Ghrelin and metabolic disorders. Current Protein and Peptide Science. 2009;10(1):2-7. [PubMed]
63. Vivenza D, Rapa A, Castellino N, et al. Ghrelin gene polymorphisms and ghrelin, insulin, IGF-I, leptin and anthropometric data in children and adolescents. European Journal of Endocrinology. 2004;151(1):127-133. [PubMed]
64. 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. Journal of Clinical Endocrinology and Metabolism. 2002;87(3):1300-1308. [PubMed]
65. Wajnrajch MP, Ten IS, Gertner JM, Leibel RL. Genomic organization of the human ghrelin gene. Journal of Endocrine Genetics. 2000;1(4):231-233.
66. Weickert MO, Loeffelholz CV, Arafat AM, et al. Euglycemic hyperinsulinemia differentially modulates circulating total and acylated-ghrelin in humans. Journal of Endocrinological Investigation. 2008;31(2):119-124. [PubMed]
67. Wiley KE, Davenport AP. Comparison of vasodilators in human internal mammary artery: ghrelin is a potent physiological antagonist of endothelin-1. British Journal of Pharmacology. 2002;136(8):1146-1152. [PMC free article] [PubMed]
68. Williams DL, Grill HJ, Cummings DE, Kaplan JM. Vagotomy dissociates short- and long-term controls of circulating ghrelin. Endocrinology. 2003;144(12):5184-5187. [PubMed] 72. Wu X, Cooper RS, Boerwinkle E, et al. Combined analysis of genomewide scans for adult height: results from the NHLBI family blood pressure program. European Journal of Human Genetics. 2003;11(3):271-274. [PubMed]
69. Zhang W, Zhao L, Lin TR, et al. Inhibition of adipogenesis by ghrelin. Molecular Biology of the Cell. 2004;15(5):2484-2491. [PMC free article] [PubMed] 74. Zorrilla EP, Iwasaki S, Moss JA, et al. Vaccination against weight gain. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(35):13226- 13231. [PMC free article] [PubMed]
Review
For citations:
, , , , , Metabolic and cardiovascular effects of ghrelin. Obesity and metabolism. 2012;9(1):3-8. (In Russ.) https://doi.org/10.14341/2071-8713-5048
Views:
1003
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0).
Email this article 
