Ghrelin in obesity, physiological and pharmacological considerations

Mini-Reviews in Medicinal Chemistry

Volumn 13, Issue 4, 2013, Pages 541-552

  Álvarez Castro, Paula ^a   Pena, Lara ^c   Cordido, Fernando ^b,c  

^a Hospital Lucus Augusti   (Spain)

^b UNIVERSITY OF A CORUÑA   (Spain)

^c HOSPITAL JUAN CANALEJO   (Spain)

Author keywords

Appetite regulation; Gastrointestinal hormones; Ghrelin; Obesity; Weight homeostasis

Indexed keywords

GHRELIN; GHRELIN RECEPTOR; GLUCOSE; GROWTH HORMONE; GROWTH HORMONE DERIVATIVE; GROWTH HORMONE RELEASING FACTOR; INSULIN; LEPTIN; LIOTHYRONINE; PEPTIDE YY; SEX HORMONE BINDING PROTEIN; THYROTROPIN;

ANOREXIA NERVOSA; BODY MASS; CACHEXIA; CHOLINERGIC STIMULATION; CHRONIC KIDNEY FAILURE; DIET; FOOD INTAKE; GROWTH HORMONE DEFICIENCY; HOMEOSTASIS; HUMAN; HYPERTHYROIDISM; HYPOPHYSIS; NONHUMAN; OBESITY; PHYSIOLOGY; PRADER WILLI SYNDROME; REVIEW; WEIGHT GAIN; WEIGHT REDUCTION;

ANTI-OBESITY AGENTS; APPETITE REGULATION; GHRELIN; GROWTH HORMONE; HUMANS; OBESITY; PITUITARY GLAND;

EID: 84875350412     PISSN: 13895575     EISSN: 18755607     Source Type: Journal    
DOI: 10.2174/1389557511313040007     Document Type: Review

References (143)

1. Eckel, R.H., Clinical practice. Nonsurgical management of obesity in adults. N Engl J Med, 2008, 358, (18), 1941-1950.
2. Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser, 2000, 894, i-xii, 1-253.
3. Ogden, C.L.; Carroll, M.D.; Curtin, L.R.; McDowell, M.A.; Tabak, C.J.; Flegal, K.M., Prevalence of overweight and obesity in the United States, 1999-2004. JAMA, 2006, 295, (13), 1549-1555.
4. Bray, G.A., Medical consequences of obesity. J Clin Endocrinol Metab, 2004, 89, (6), 2583-2589.
5. Haslam, D.W.; James, W.P., Obesity. Lancet, 2005, 366, (9492), 1197-1209.
6. Colditz, G.A.; Willett, W.C.; Rotnitzky, A.; Manson, J.E., Weight gain as a risk factor for clinical diabetes mellitus in women. Ann Intern Med, 1995, 122, (7), 481-486.
7. Banegas, J.R.; Lopez-Garcia, E.; Gutierrez-Fisac, J.L.; Guallar-Castillon, P.; Rodriguez-Artalejo, F., A simple estimate of mortality attributable to excess weight in the European Union. Eur J Clin Nutr, 2003, 57, (2), 201-208.
8. Adams, K.F.; Schatzkin, A.; Harris, T.B.; Kipnis, V.; Mouw, T.; Ballard-Barbash, R.; Hollenbeck, A.; Leitzmann, M.F., Overweight, obesity, and mortality in a large prospective cohort of persons 50 to 71 years old. N Engl J Med, 2006, 355, (8), 763-778.
9. Berrington de Gonzalez, A.; Hartge, P.; Cerhan, J.R.; Flint, A.J.; Hannan, L.; MacInnis, R.J.; Moore, S.C.; Tobias, G.S.; Anton-Culver, H.; Freeman, L.B.; Beeson, W.L.; Clipp, S.L.; English, D.R.; Folsom, A.R.; Freedman, D.M.; Giles, G.; Hakansson, N.; Henderson, K.D.; Hoffman-Bolton, J.; Hoppin, J.A.; Koenig, K.L.; Lee, I.M.; Linet, M.S.; Park, Y.; Pocobelli, G.; Schatzkin, A.; Sesso, H.D.; Weiderpass, E.; Willcox, B.J.; Wolk, A.; Zeleniuch-Jacquotte, A.; Willett, W.C.; Thun, M.J., Body-mass index and mortality among 1.46 million white adults. N Engl J Med, 2010, 363, (23), 2211-2219.
10. von Lengerke, T.; Reitmeir, P.; John, J., [Direct medical costs of (severe) obesity: a bottom-up assessment of over-vs. normalweight adults in the KORA-study region (Augsburg, Germany)]. Gesundheitswesen, 2006, 68, (2), 110-115.
11. Flegal, K.M.; Carroll, M.D.; Ogden, C.L.; Johnson, C.L., Prevalence and trends in obesity among US adults, 1999-2000. JAMA, 2002, 288, (14), 1723-1727.
12. Arrizabalaga, J.J.; Masmiquel, L.; Vidal, J.; Calanas-Continente, A.; Diaz-Fernandez, M.J.; Garcia-Luna, P.P.; Monereo, S.; Moreiro, J.; Moreno, B.; Ricart, W.; Cordido, F., [Overweight and obesity in adults: recommendations and treatment algorithms]. Med Clin (Barc), 2004, 122, (3), 104-110.
13. Poulose, B.K.; Holzman, M.D.; Zhu, Y.; Smalley, W.; Richards, W.O.; Wright, J.K.; Melvin, W.; Griffin, M.R., National variations in morbid obesity and bariatric surgery use. J Am Coll Surg, 2005, 201, (1), 77-84.
14. Mozaffarian, D.; Hao, T.; Rimm, E.B.; Willett, W.C.; Hu, F.B., Changes in diet and lifestyle and long-term weight gain in women and men. N Engl J Med, 2011, 364, (25), 2392-2404.
15. Gutierrez-Fisac, J.L.; Guallar-Castillon, P.; Leon-Munoz, L.M.; Graciani, A.; Banegas, J.R.; Rodriguez-Artalejo, F., Prevalence of general and abdominal obesity in the adult population of Spain, 2008-2010: the ENRICA study. Obes Rev, 2011.
16. Cordido, F.; Garcia-Buela, J.; Sangiao-Alvarellos, S.; Martinez, T.; Vidal, O., The decreased growth hormone response to growth hormone releasing hormone in obesity is associated to cardiometabolic risk factors. Mediators Inflamm, 2010, 2010, 434562.
17. Alvarez-Castro, P.; Sangiao-Alvarellos, S.; Brandon-Sanda, I.; Cordido, F., Endocrine function in obesity. Endocrinol Nutr, 2011, 58, (8), 422-432.
18. Bowers, C.Y., Growth hormone-releasing peptide (GHRP). Cell Mol Life Sci, 1998, 54, (12), 1316-1329.
19. Smith, R.G., Development of growth hormone secretagogues. Endocr Rev, 2005, 26, (3), 346-360.
20. Smith, R.G.; Cheng, K.; Schoen, W.R.; Pong, S.S.; Hickey, G.; Jacks, T.; Butler, B.; Chan, W.W.; Chaung, L.Y.; Judith, F.; et al., A nonpeptidyl growth hormone secretagogue. Science, 1993, 260, (5114), 1640-1643.
21. Smith, R.G.; Leonard, R.; Bailey, A.R.; Palyha, O.; Feighner, S.; Tan, C.; McKee, K.K.; Pong, S.S.; Griffin, P.; Howard, A., Growth hormone secretagogue receptor family members and ligands. Endocrine, 2001, 14, (1), 9-14.
22. Smith, R.G.; Sun, Y.; Betancourt, L.; Asnicar, M., Growth hormone secretagogues: prospects and potential pitfalls. Best Pract Res Clin Endocrinol Metab, 2004, 18, (3), 333-347.
23. Isidro, M.L.; Cordido, F., Growth hormone secretagogues. Comb Chem High Throughput Screen, 2006, 9, (3), 175-180.
24. Smith, R.G.; Feighner, S.; Prendergast, K.; Guan, X.; Howard, A., A New Orphan Receptor Involved in Pulsatile Growth Hormone Release. Trends in endocrinology and metabolism: TEM, 1999, 10, (4), 128-135.
25. Howard, A.D.; Feighner, S.D.; Cully, D.F.; Arena, J.P.; Liberator, P.A.; Rosenblum, C.I.; Hamelin, M.; Hreniuk, D.L.; Palyha, O.C.; Anderson, J.; Paress, P.S.; Diaz, C.; Chou, M.; Liu, K.K.; McKee, K.K.; Pong, S.S.; Chaung, L.Y.; Elbrecht, A.; Dashkevicz, M.; Heavens, R.; Rigby, M.; Sirinathsinghji, D.J.; Dean, D.C.; Melillo, D.G.; Patchett, A.A.; Nargund, R.; Griffin, P.R.; DeMartino, J.A.; Gupta, S.K.; Schaeffer, J.M.; Smith, R.G.; Van der Ploeg, L.H., A receptor in pituitary and hypothalamus that functions in growth hormone release. Science, 1996, 273, (5277), 974-977.
26. 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, (6762), 656-660.
27. Kojima, M.; Kangawa, K., Ghrelin: structure and function. Physiol Rev, 2005, 85, (2), 495-522.
28. Broglio, F.; Benso, A.; Gottero, C.; Prodam, F.; Gauna, C.; Filtri, L.; Arvat, E.; van der Lely, A.J.; Deghenghi, R.; Ghigo, E., Nonacylated ghrelin does not possess the pituitaric and pancreatic endocrine activity of acylated ghrelin in humans. J Endocrinol Invest, 2003, 26, (3), 192-196.
29. van der Lely, A.J.; Tschop, M.; Heiman, M.L.; Ghigo, E., Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr Rev, 2004, 25, (3), 426-457.
30. 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 ghrelinlike immunoreactivity levels in humans. J Clin Endocrinol Metab, 2001, 86, (10), 4753-4758.
31. Yang, J.; Brown, M.S.; Liang, G.; Grishin, N.V.; Goldstein, J.L., Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell, 2008, 132, (3), 387-396.
32. Pemberton, C.J.; Richards, A.M., Biochemistry of ghrelin precursor peptides. Vitam Horm, 2008, 77, 13-30.
33. Ingelsson, E.; Larson, M.G.; Yin, X.; Wang, T.J.; Meigs, J.B.; Lipinska, I.; Benjamin, E.J.; Keaney, J.F., Jr.; Vasan, R.S., Circulating ghrelin, leptin, and soluble leptin receptor concentrations and cardiometabolic risk factors in a communitybased sample. J Clin Endocrinol Metab, 2008, 93, (8), 3149-3157.
34. Blatnik, M.; Soderstrom, C.I., A practical guide for the stabilization of acylghrelin in human blood collections. Clin Endocrinol (Oxf), 2011, 74, (3), 325-331.
35. 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, 476, (1-2), 87-95.
36. Thompson, N.M.; Gill, D.A.; Davies, R.; Loveridge, N.; Houston, P.A.; Robinson, I.C.; 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, (1), 234-242.
37. Veldhuis, J.D.; Bowers, C.Y., Integrating GHS into the Ghrelin System. Int J Pept, 2010, 2010.
38. Cruz, C.R.; Smith, R.G., The growth hormone secretagogue receptor. Vitam Horm, 2008, 77, 47-88.
39. Tschop, M.; Smiley, D.L.; Heiman, M.L., Ghrelin induces adiposity in rodents. Nature, 2000, 407, (6806), 908-913.
40. Shuto, Y.; Shibasaki, T.; Otagiri, A.; Kuriyama, H.; Ohata, H.; Tamura, H.; Kamegai, J.; Sugihara, H.; Oikawa, S.; Wakabayashi, I., Hypothalamic growth hormone secretagogue receptor regulates growth hormone secretion, feeding, and adiposity. J Clin Invest, 2002, 109, (11), 1429-1436.
41. Cummings, D.E.; Clement, K.; Purnell, J.Q.; Vaisse, C.; Foster, K.E.; Frayo, R.S.; Schwartz, M.W.; Basdevant, A.; Weigle, D.S., Elevated plasma ghrelin levels in Prader Willi syndrome. Nat Med, 2002, 8, (7), 643-644.
42. Ravussin, E.; Tschop, M.; Morales, S.; Bouchard, C.; Heiman, M.L., Plasma ghrelin concentration and energy balance: overfeeding and negative energy balance studies in twins. J Clin Endocrinol Metab, 2001, 86, (9), 4547-4551.
43. Zhang, J.V.; Ren, P.G.; Avsian-Kretchmer, O.; Luo, C.W.; Rauch, R.; Klein, C.; Hsueh, A.J., Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake. Science, 2005, 310, (5750), 996-999.
44. Tremblay, F.; Perreault, M.; Klaman, L.D.; Tobin, J.F.; Smith, E.; Gimeno, R.E., Normal food intake and body weight in mice lacking the G protein-coupled receptor GPR39. Endocrinology, 2007, 148, (2), 501-506.
45. Holst, B.; Egerod, K.L.; Schild, E.; Vickers, S.P.; Cheetham, S.; Gerlach, L.O.; Storjohann, L.; Stidsen, C.E.; Jones, R.; Beck-Sickinger, A.G.; Schwartz, T.W., GPR39 signaling is stimulated by zinc ions but not by obestatin. Endocrinology, 2007, 148, (1), 13-20.
46. Yamamoto, D.; Ikeshita, N.; Daito, R.; Herningtyas, E.H.; Toda, K.; Takahashi, K.; Iida, K.; Takahashi, Y.; Kaji, H.; Chihara, K.; Okimura, Y., Neither intravenous nor intracerebroventricular administration of obestatin affects the secretion of GH, PRL, TSH and ACTH in rats. Regul Pept, 2007, 138, (2-3), 141-144.
47. Cummings, D.E.; Purnell, J.Q.; Frayo, R.S.; Schmidova, K.; Wisse, B.E.; Weigle, D.S., A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes, 2001, 50, (8), 1714-1719.
48. Cummings, D.E.; Weigle, D.S.; Frayo, R.S.; Breen, P.A.; Ma, M.K.; Dellinger, E.P.; Purnell, J.Q., Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med, 2002, 346, (21), 1623-1630.
49. Norrelund, H.; Hansen, T.K.; Orskov, H.; Hosoda, H.; Kojima, M.; Kangawa, K.; Weeke, J.; Moller, N.; Christiansen, J.S.; Jorgensen, J.O., Ghrelin immunoreactivity in human plasma is suppressed by somatostatin. Clin Endocrinol (Oxf), 2002, 57, (4), 539-546.
50. Hansen, T.K.; Dall, R.; Hosoda, H.; Kojima, M.; Kangawa, K.; Christiansen, J.S.; Jorgensen, J.O., Weight loss increases circulating levels of ghrelin in human obesity. Clin Endocrinol (Oxf), 2002, 56, (2), 203-206.
51. Otto, B.; Cuntz, U.; Fruehauf, E.; Wawarta, R.; Folwaczny, C.; Riepl, R.L.; Heiman, M.L.; Lehnert, P.; Fichter, M.; Tschop, M., Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa. Eur J Endocrinol, 2001, 145, (5), 669-673.
52. Tschop, M.; Weyer, C.; Tataranni, P.A.; Devanarayan, V.; Ravussin, E.; Heiman, M.L., Circulating ghrelin levels are decreased in human obesity. Diabetes, 2001, 50, (4), 707-709.
53. Foster-Schubert, K.E.; Overduin, J.; Prudom, C.E.; Liu, J.; Callahan, H.S.; Gaylinn, B.D.; Thorner, M.O.; Cummings, D.E., Acyl and total ghrelin are suppressed strongly by ingested proteins, weakly by lipids, and biphasically by carbohydrates. J Clin Endocrinol Metab, 2008, 93, (5), 1971-1979.
54. Takachi, K.; Doki, Y.; Ishikawa, O.; Miyashiro, I.; Sasaki, Y.; Ohigashi, H.; Murata, K.; Nakajima, H.; Hosoda, H.; Kangawa, K.; Sasakuma, F.; Imaoka, S., Postoperative ghrelin levels and delayed recovery from body weight loss after distal or total gastrectomy. J Surg Res, 2006, 130, (1), 1-7.
55. Shiiya, T.; Nakazato, M.; Mizuta, M.; Date, Y.; Mondal, M.S.; 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, (1), 240-244.
56. Williams, D.L.; Cummings, D.E.; Grill, H.J.; Kaplan, J.M., Mealrelated ghrelin suppression requires postgastric feedback. Endocrinology, 2003, 144, (7), 2765-2767.
57. le Roux, C.W.; Patterson, M.; Vincent, R.P.; Hunt, C.; Ghatei, M.A.; Bloom, S.R., Postprandial plasma ghrelin is suppressed proportional to meal calorie content in normal-weight but not obese subjects. J Clin Endocrinol Metab, 2005, 90, (2), 1068-1071.
58. Perez-Fontan, M.; Cordido, F.; Rodriguez-Carmona, A.; Garcia-Naveiro, R.; Isidro, M.L.; Villaverde, P.; Garcia-Buela, J., Acute plasma ghrelin and leptin responses to oral feeding or intraperitoneal hypertonic glucose-based dialysate in patients with chronic renal failure. Kidney Int, 2005, 68, (6), 2877-2885.
59. Blom, W.A.; Stafleu, A.; de Graaf, C.; Kok, F.J.; Schaafsma, G.; Hendriks, H.F., Ghrelin response to carbohydrate-enriched breakfast is related to insulin. Am J Clin Nutr, 2005, 81, (2), 367-375.
60. Haqq, A.M.; Farooqi, I.S.; O'Rahilly, S.; Stadler, D.D.; Rosenfeld, R.G.; Pratt, K.L.; LaFranchi, S.H.; Purnell, J.Q., Serum ghrelin levels are inversely correlated with body mass index, age, and insulin concentrations in normal children and are markedly increased in Prader-Willi syndrome. J Clin Endocrinol Metab, 2003, 88, (1), 174-178.
61. Caixas, A.; Bashore, C.; Nash, W.; Pi-Sunyer, F.; Laferrere, B., Insulin, unlike food intake, does not suppress ghrelin in human subjects. J Clin Endocrinol Metab, 2002, 87, (4), 1902.
62. McLaughlin, T.; Abbasi, F.; Lamendola, C.; Frayo, R.S.; Cummings, D.E., Plasma ghrelin concentrations are decreased in insulin-resistant obese adults relative to equally obese insulin-sensitive controls. J Clin Endocrinol Metab, 2004, 89, (4), 1630-1635.
63. Espelund, U.; Hansen, T.K.; Hojlund, K.; Beck-Nielsen, H.; Clausen, J.T.; Hansen, B.S.; Orskov, H.; Jorgensen, J.O.; Frystyk, J., Fasting unmasks a strong inverse association between ghrelin and cortisol in serum: studies in obese and normal-weight subjects. J Clin Endocrinol Metab, 2005, 90, (2), 741-746.
64. Koutkia, P.; Schurgin, S.; Berry, J.; Breu, J.; Lee, B.S.; Klibanski, A.; Grinspoon, S., Reciprocal changes in endogenous ghrelin and growth hormone during fasting in healthy women. Am J Physiol Endocrinol Metab, 2005, 289, (5), E814-822.
65. Alvarez-Castro, P.; Isidro, M.L.; Garcia-Buela, J.; Leal-Cerro, A.; Broglio, F.; Tassone, F.; Ghigo, E.; Dieguez, C.; Casanueva, F.F.; Cordido, F., Marked GH secretion after ghrelin alone or combined with GH-releasing hormone (GHRH) in obese patients. Clin Endocrinol (Oxf), 2004, 61, (2), 250-255.
66. Eden Engstrom, B.; Burman, P.; Holdstock, C.; Ohrvall, M.; Sundbom, M.; Karlsson, F.A., Effects of gastric bypass on the GH/IGF-I axis in severe obesity--and a comparison with GH deficiency. Eur J Endocrinol, 2006, 154, (1), 53-59.
67. Isidro, M.L.; Nemina, R.; Garcia-Buela, J.; Sangiao-Alvarellos, S.; Cordido, F., Effect of oral glucose on acylated and total ghrelin secretion in acromegalic patients. Neuro Endocrinol Lett, 2007, 28, (5), 596-603.
68. Nass, R.; Farhy, L.S.; Liu, J.; Prudom, C.E.; Johnson, M.L.; Veldhuis, P.; Pezzoli, S.S.; Oliveri, M.C.; Gaylinn, B.D.; Geysen, H.M.; Thorner, M.O., Evidence for acyl-ghrelin modulation of growth hormone release in the fed state. J Clin Endocrinol Metab, 2008, 93, (5), 1988-1994.
69. Tritos, N.A.; Kokkotou, E.G., The physiology and potential clinical applications of ghrelin, a novel peptide hormone. Mayo Clin Proc, 2006, 81, (5), 653-660.
70. Gimenez-Palop, O.; Gimenez-Perez, G.; Mauricio, D.; Gonzalez-Clemente, J.M.; Potau, N.; Berlanga, E.; Trallero, R.; Laferrere, B.; Caixas, A., A lesser postprandial suppression of plasma ghrelin in Prader-Willi syndrome is associated with low fasting and a blunted postprandial PYY response. Clin Endocrinol (Oxf), 2007, 66, (2), 198-204.
71. Tolle, V.; Kadem, M.; Bluet-Pajot, M.T.; Frere, D.; Foulon, C.; Bossu, C.; Dardennes, R.; Mounier, C.; Zizzari, P.; Lang, F.; Epelbaum, J.; Estour, B., Balance in ghrelin and leptin plasma levels in anorexia nervosa patients and constitutionally thin women. J Clin Endocrinol Metab, 2003, 88, (1), 109-116.
72. Korner, J.; Inabnet, W.; Conwell, I.M.; Taveras, C.; Daud, A.; Olivero-Rivera, L.; Restuccia, N.L.; Bessler, M., Differential effects of gastric bypass and banding on circulating gut hormone and leptin levels. Obesity (Silver Spring), 2006, 14, (9), 1553-1561.
73. Bose, M.; Olivan, B.; Teixeira, J.; Pi-Sunyer, F.X.; Laferrere, B., Do Incretins play a role in the remission of type 2 diabetes after gastric bypass surgery: What are the evidence? Obes Surg, 2009, 19, (2), 217-229.
74. Scerif, M.; Goldstone, A.P.; Korbonits, M., Ghrelin in obesity and endocrine diseases. Mol Cell Endocrinol, 2011, 340, (1), 15-25.
75. Mackelvie, K.J.; Meneilly, G.S.; Elahi, D.; Wong, A.C.; Barr, S.I.; Chanoine, J.P., Regulation of appetite in lean and obese adolescents after exercise: role of acylated and desacyl ghrelin. J Clin Endocrinol Metab, 2007, 92, (2), 648-654.
76. King, J.A.; Wasse, L.K.; Ewens, J.; Crystallis, K.; Emmanuel, J.; Batterham, R.L.; Stensel, D.J., Differential Acylated Ghrelin, Peptide YY3-36, Appetite, and Food Intake Responses to Equivalent Energy Deficits Created by Exercise and Food Restriction. J Clin Endocrinol Metab, 2011, 96, (4), 1114-1121.
77. Labayen, I.; Ortega, F.B.; Ruiz, J.R.; Lasa, A.; Simon, E.; Margareto, J., Role of baseline leptin and ghrelin levels on body weight and fat mass changes after an energy-restricted diet intervention in obese women: effects on energy metabolism. J Clin Endocrinol Metab, 2011, 96, (6), E996-E1000.
78. Sumithran, P.; Prendergast, L.A.; Delbridge, E.; Purcell, K.; Shulkes, A.; Kriketos, A.; Proietto, J., Long-term persistence of hormonal adaptations to weight loss. N Engl J Med, 2011, 365, (17), 1597-1604.
79. Cordido, F.; Sangiao-Alvarellos, S.; Perez-Fontan, M., Long-term hormonal adaptations to weight loss. N Engl J Med, 2012, 366, (4), 380-381; author reply 382.
80. Rodriguez-Carmona, A.; Perez-Fontan, M.; Guitian, A.; Peteiro, J.; Garcia-Falcon, T.; Lopez-Muniz, A.; Garcia-Buela, J.; Cordido, F., Effect of low-GDP bicarbonate-lactate-buffered peritoneal dialysis solutions on plasma levels of adipokines and gut appetiteregulatory peptides. A randomized crossover study. Nephrol Dial Transplant, 2012, 27, (1), 369-374.
81. Diz-Lois, M.T.; Garcia-Buela, J.; Suarez, F.; Sangiao-Alvarellos, S.; Vidal, O.; Cordido, F., Fasting and postprandial plasma ghrelin levels are decreased in patients with liver failure previous to liver transplantation. Endocrine, 2009, 35, (3), 467-476.
82. Diz-Lois, M.T.; Garcia-Buela, J.; Suarez, F.; Sangiao-Alvarellos, S.; Vidal, O.; Cordido, F., Altered fasting and postprandial plasma ghrelin levels in patients with liver failure are normalized after liver transplantation. Eur J Endocrinol, 2010, 163, (4), 609-616.
83. Perez-Fontan, M.; Cordido, F.; Rodriguez-Carmona, A.; Peteiro, J.; Garcia-Naveiro, R.; Garcia-Buela, J., Plasma ghrelin levels in patients undergoing haemodialysis and peritoneal dialysis. Nephrol Dial Transplant, 2004, 19, (8), 2095-2100.
84. Kluge, M.; Schüssler, P.; Schmidt, D.; Uhr, M.; Steiger, A., Ghrelin Suppresses Secretion of Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH) in Women. Journal of Clinical Endocrinology & Metabolism, 2012, 97, (3), E448-E451.
85. Broglio, F.; Benso, A.; Gottero, C.; Prodam, F.; Grottoli, S.; Tassone, F.; Maccario, M.; Casanueva, F.F.; Dieguez, C.; Deghenghi, R.; Ghigo, E.; Arvat, E., Effects of glucose, free fatty acids or arginine load on the GH-releasing activity of ghrelin in humans. Clin Endocrinol (Oxf), 2002, 57, (2), 265-271.
86. Rico, M.; Rueda, V.; Lorenzo, M.T.; Nunez, A.; De la Cruz, L.F., Effect of growth hormone-releasing peptide 1-6 on GH secretionstimulated by GHRH and pyridostigmine in lambs. J Physiol Biochem, 1998, 54, (2), 67-76.
87. Popovic, V.; Damjanovic, S.; Micic, D.; Djurovic, M.; Dieguez, C.; Casanueva, F.F., Blocked growth hormone-releasing peptide (GHRP-6)-induced GH secretion and absence of the synergic action of GHRP-6 plus GH-releasing hormone in patients with hypothalamopituitary disconnection: evidence that GHRP-6 main action is exerted at the hypothalamic level. J Clin Endocrinol Metab, 1995, 80, (3), 942-947.
88. Cordido, F.; Penalva, A.; Dieguez, C.; Casanueva, F.F., Massive growth hormone (GH) discharge in obese subjects after the combined administration of GH-releasing hormone and GHRP-6: evidence for a marked somatotroph secretory capability in obesity. J Clin Endocrinol Metab, 1993, 76, (4), 819-823.
89. Tassone, F.; Broglio, F.; Destefanis, S.; Rovere, S.; Benso, A.; Gottero, C.; Prodam, F.; Rossetto, R.; Gauna, C.; van der Lely, A.J.; Ghigo, E.; Maccario, M., Neuroendocrine and metabolic effects of acute ghrelin administration in human obesity. J Clin Endocrinol Metab, 2003, 88, (11), 5478-5483.
90. Alvarez, P.; Isidro, L.; Leal-Cerro, A.; Casanueva, F.F.; Dieguez, C.; Cordido, F., Effect of withdrawal of somatostatin plus GHreleasing hormone as a stimulus of GH secretion in obesity. Clin Endocrinol (Oxf), 2002, 56, (4), 487-492.
91. Cordido, F.; Penalva, A.; Peino, R.; Casanueva, F.F.; Dieguez, C., Effect of combined administration of growth hormone (GH)-releasing hormone, GH-releasing peptide-6, and pyridostigmine in normal and obese subjects. Metabolism, 1995, 44, (6), 745-748.
92. Pombo, M.; Pombo, C.M.; Astorga, R.; Cordido, F.; Popovic, V.; Garcia-Mayor, R.V.; Dieguez, C.; Casanueva, F.F., Regulation of growth hormone secretion by signals produced by the adipose tissue. J Endocrinol Invest, 1999, 22, (5 Suppl), 22-26.
93. Sun, Y.; Ahmed, S.; Smith, R.G., Deletion of ghrelin impairs neither growth nor appetite. Mol Cell Biol, 2003, 23, (22), 7973-7981.
94. Pantel, J.; Legendre, M.; Cabrol, S.; Hilal, L.; Hajaji, Y.; Morisset, S.; Nivot, S.; Vie-Luton, M.P.; Grouselle, D.; de Kerdanet, M.; Kadiri, A.; Epelbaum, J.; Le Bouc, Y.; Amselem, S., Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature. J Clin Invest, 2006, 116, (3), 760-768.
95. Outeirino-Blanco, E.; Garcia-Buela, J.; Sangiao-Alvarellos, S.; Pertega-Diaz, S.; Martinez-Ramonde, T.; Cordido, F., Growth Hormone, Ghrelin and Peptide YY Secretion after Oral Glucose Administration in Healthy and Obese Women. Horm Metab Res, 2011, 43, (8), 580-586.
96. Outeirino-Blanco, E.; Garcia-Buela, J.; Sangiao-Alvarellos, S.; Brandon, I.; Pena, L.; Pertega-Diaz, S.; Martinez, T.; Cordido, F., Sexual Dimorphism on Growth Hormone Secretion after Oral Glucose Administration. Horm Metab Res, 2012.
97. Nass, R.; Gaylinn, B.D.; Thorner, M.O., The role of ghrelin in GH secretion and GH disorders. Mol Cell Endocrinol, 2011, 340, (1), 10-14.
98. Zhao, T.J.; Liang, G.; Li, R.L.; Xie, X.; Sleeman, M.W.; Murphy, A.J.; Valenzuela, D.M.; Yancopoulos, G.D.; Goldstein, J.L.; Brown, M.S., Ghrelin O-acyltransferase (GOAT) is essential for growth hormone-mediated survival of calorie-restricted mice. Proc Natl Acad Sci U S A, 2010, 107, (16), 7467-7472.
99. Yi, C.X.; Heppner, K.M.; Kirchner, H.; Tong, J.; Bielohuby, M.; Gaylinn, B.D.; Muller, T.D.; Bartley, E.; Davis, H.W.; Zhao, Y.; Joseph, A.; Kruthaupt, T.; Ottaway, N.; Kabra, D.; Habegger, K.M.; Benoit, S.C.; Bidlingmaier, M.; Thorner, M.O.; Perez-Tilve, D.; Tschop, M.H.; Pfluger, P.T., The GOAT-ghrelin system is not essential for hypoglycemia prevention during prolonged calorie restriction. PLoS ONE, 2012, 7, (2), e32100.
100. 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, (6817), 194-198.
101. Zigman, J.M.; Nakano, Y.; Coppari, R.; Balthasar, N.; Marcus, J.N.; Lee, C.E.; Jones, J.E.; Deysher, A.E.; Waxman, A.R.; White, R.D.; Williams, T.D.; Lachey, J.L.; Seeley, R.J.; Lowell, B.B.; Elmquist, J.K., Mice lacking ghrelin receptors resist the development of diet-induced obesity. J Clin Invest, 2005, 115, (12), 3564-3572.
102. Cummings, D.E.; Frayo, R.S.; Marmonier, C.; Aubert, R.; Chapelot, D., Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily without time-and food-related cues. Am J Physiol Endocrinol Metab, 2004, 287, (2), E297-304.
103. Wren, A.M.; Seal, L.J.; Cohen, M.A.; Brynes, A.E.; Frost, G.S.; Murphy, K.G.; Dhillo, W.S.; Ghatei, M.A.; Bloom, S.R., Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab, 2001, 86, (12), 5992.
104. Cummings, D.E.; Foster, K.E., Ghrelin-leptin tango in body-weight regulation. Gastroenterology, 2003, 124, (5), 1532-1535.
105. Wortley, K.E.; del Rincon, J.P.; Murray, J.D.; Garcia, K.; Iida, K.; Thorner, M.O.; Sleeman, M.W., Absence of ghrelin protects against early-onset obesity. J Clin Invest, 2005, 115, (12), 3573-3578.
106. Coll, A.P.; Farooqi, I.S.; O'Rahilly, S., The hormonal control of food intake. Cell, 2007, 129, (2), 251-262.
107. Guyenet, S.J.; Schwartz, M.W., Regulation of Food Intake, Energy Balance, and Body Fat Mass: Implications for the Pathogenesis and Treatment of Obesity. Journal of Clinical Endocrinology & Metabolism, 2012, 97, (3), 745-755.
108. Wren, A.M.; Small, C.J.; Ward, H.L.; Murphy, K.G.; Dakin, C.L.; Taheri, S.; Kennedy, A.R.; Roberts, G.H.; Morgan, D.G.; Ghatei, M.A.; Bloom, S.R., The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology, 2000, 141, (11), 4325-4328.
109. Valassi, E.; Scacchi, M.; Cavagnini, F., Neuroendocrine control of food intake. Nutr Metab Cardiovasc Dis, 2008, 18, (2), 158-168.
110. Asakawa, A.; Inui, A.; Kaga, T.; Yuzuriha, H.; Nagata, T.; Fujimiya, M.; Katsuura, G.; Makino, S.; Fujino, M.A.; Kasuga, M., A role of ghrelin in neuroendocrine and behavioral responses to stress in mice. Neuroendocrinology, 2001, 74, (3), 143-147.
111. Bewick, G.A.; Gardiner, J.V.; Dhillo, W.S.; Kent, A.S.; White, N.E.; Webster, Z.; Ghatei, M.A.; Bloom, S.R., Post-embryonic ablation of AgRP neurons in mice leads to a lean, hypophagic phenotype. FASEB J, 2005, 19, (12), 1680-1682.
112. Lim, C.T.; Kola, B.; Korbonits, M., AMPK as a mediator of hormonal signalling. J Mol Endocrinol, 2010, 44, (2), 87-97.
113. Bewick, G.A.; Kent, A.; Campbell, D.; Patterson, M.; Ghatei, M.A.; Bloom, S.R.; Gardiner, J.V., Mice with hyperghrelinemia are hyperphagic and glucose intolerant and have reduced leptin sensitivity. Diabetes, 2009, 58, (4), 840-846.
114. Sangiao-Alvarellos, S.; Vazquez, M.J.; Varela, L.; Nogueiras, R.; Saha, A.K.; Cordido, F.; Lopez, M.; Dieguez, C., Central ghrelin regulates peripheral lipid metabolism in a growth hormoneindependent fashion. Endocrinology, 2009, 150, (10), 4562-4574.
115. Sangiao-Alvarellos, S.; Varela, L.; Vazquez, M.J.; Da Boit, K.; Saha, A.K.; Cordido, F.; Dieguez, C.; Lopez, M., Influence of Ghrelin and growth hormone deficiency on AMP-activated protein kinase and hypothalamic lipid metabolism. J Neuroendocrinol, 2010, 22, (6), 543-556.
116. Sangiao-Alvarellos, S.; Helmling, S.; Vazquez, M.J.; Klussmann, S.; Cordido, F., Ghrelin neutralization during fasting-refeeding cycle impairs the recuperation of body weight and alters hepatic energy metabolism. Mol Cell Endocrinol, 2011, 335, (2), 177-188.
117. Briggs, D.I.; Enriori, P.J.; Lemus, M.B.; Cowley, M.A.; Andrews, Z.B., Diet-induced obesity causes ghrelin resistance in arcuate NPY/AgRP neurons. Endocrinology, 2010, 151, (10), 4745-4755.
118. Chuang, J.C.; Perello, M.; Sakata, I.; Osborne-Lawrence, S.; Savitt, J.M.; Lutter, M.; Zigman, J.M., Ghrelin mediates stress-induced foodreward behavior in mice. J Clin Invest, 2011, 121, (7), 2684-2692.
119. Nass, R.; Gaylinn, B.D.; Thorner, M.O., The ghrelin axis in disease: potential therapeutic indications. Mol Cell Endocrinol, 2011, 340, (1), 106-110.
120. Holst, B.; Cygankiewicz, A.; Jensen, T.H.; Ankersen, M.; Schwartz, T.W., High constitutive signaling of the ghrelin receptor--identification of a potent inverse agonist. Mol Endocrinol, 2003, 17, (11), 2201-2210.
121. Holst, B.; Holliday, N.D.; Bach, A.; Elling, C.E.; Cox, H.M.; Schwartz, T.W., Common structural basis for constitutive activity of the ghrelin receptor family. J Biol Chem, 2004, 279, (51), 53806-53817.
122. Holst, B.; Brandt, E.; Bach, A.; Heding, A.; Schwartz, T.W., Nonpeptide and peptide growth hormone secretagogues act both as ghrelin receptor agonist and as positive or negative allosteric modulators of ghrelin signaling. Mol Endocrinol, 2005, 19, (9), 2400-2411.
123. Holst, B.; Mokrosinski, J.; Lang, M.; Brandt, E.; Nygaard, R.; Frimurer, T.M.; Beck-Sickinger, A.G.; Schwartz, T.W., Identification of an efficacy switch region in the ghrelin receptor responsible for interchange between agonism and inverse agonism. J Biol Chem, 2007, 282, (21), 15799-15811.
124. Mericq, V.; Cassorla, F.; Salazar, T.; Avila, A.; Iniguez, G.; Bowers, C.Y.; Merriam, G.R., Effects of eight months treatment with graded doses of a growth hormone (GH)-releasing peptide in GH-deficient children. J Clin Endocrinol Metab, 1998, 83, (7), 2355-2360.
125. Nass, R.; Pezzoli, S.S.; Oliveri, M.C.; Patrie, J.T.; Harrell, F.E., Jr.; Clasey, J.L.; Heymsfield, S.B.; Bach, M.A.; Vance, M.L.; Thorner, M.O., Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial. Ann Intern Med, 2008, 149, (9), 601-611.
126. Wortley, K.E.; Anderson, K.D.; Garcia, K.; Murray, J.D.; Malinova, L.; Liu, R.; Moncrieffe, M.; Thabet, K.; Cox, H.J.; Yancopoulos, G.D.; Wiegand, S.J.; Sleeman, M.W., Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel preference. Proc Natl Acad Sci U S A, 2004, 101, (21), 8227-8232.
127. Muccioli, G.; Tschop, M.; Papotti, M.; Deghenghi, R.; Heiman, M.; Ghigo, E., Neuroendocrine and peripheral activities of ghrelin: implications in metabolism and obesity. Eur J Pharmacol, 2002, 440, (2-3), 235-254.
128. Cordido, F.; Isidro, M.L.; Nemina, R.; Sangiao-Alvarellos, S., Ghrelin and growth hormone secretagogues, physiological and pharmacological aspect. Curr Drug Discov Technol, 2009, 6, (1), 34-42.
129. Strasser, F.; Lutz, T.A.; Maeder, M.T.; Thuerlimann, B.; Bueche, D.; Tschop, M.; Kaufmann, K.; Holst, B.; Brandle, M.; von Moos, R.; Demmer, R.; Cerny, T., Safety, tolerability and pharmacokinetics of intravenous ghrelin for cancer-related anorexia/cachexia: a randomised, placebo-controlled, double-blind, double-crossover study. Br J Cancer, 2008, 98, (2), 300-308.
130. Rasmussen, M.H., Obesity, growth hormone and weight loss. Mol Cell Endocrinol, 2010, 316, (2), 147-153.
131. Taub, D.D.; Murphy, W.J.; Longo, D.L., Rejuvenation of the aging thymus: growth hormone-mediated and ghrelin-mediated signaling pathways. Curr Opin Pharmacol, 2010, 10, (4), 408-424.
132. Baatar, D.; Patel, K.; Taub, D.D., The effects of ghrelin on inflammation and the immune system. Mol Cell Endocrinol, 2011, 340, (1), 44-58.
133. Schellekens, H.; Dinan, T.G.; Cryan, J.F., Lean mean fat reducing "ghrelin" machine: hypothalamic ghrelin and ghrelin receptors as therapeutic targets in obesity. Neuropharmacology, 2010, 58, (1), 2-16.
134. Zorrilla, E.P.; Iwasaki, S.; Moss, J.A.; Chang, J.; Otsuji, J.; Inoue, K.; Meijler, M.M.; Janda, K.D., Vaccination against weight gain. Proc Natl Acad Sci U S A, 2006, 103, (35), 13226-13231.
135. Mokrosinski, J.; Holst, B., Modulation of the constitutive activity of the ghrelin receptor by use of pharmacological tools and mutagenesis. Methods Enzymol, 2010, 484, 53-73.
136. Moulin, A.; Demange, L.; Ryan, J.; Mousseaux, D.; Sanchez, P.; Berge, G.; Gagne, D.; Perrissoud, D.; Locatelli, V.; Torsello, A.; Galleyrand, J.C.; Fehrentz, J.A.; Martinez, J., New trisubstituted 1,2,4-triazole derivatives as potent ghrelin receptor antagonists. 3. Synthesis and pharmacological in vitro and in vivo evaluations. J Med Chem, 2008, 51, (3), 689-693.
137. Beck, B.; Richy, S.; Stricker-Krongrad, A., Feeding response to ghrelin agonist and antagonist in lean and obese Zucker rats. Life Sci, 2004, 76, (4), 473-478.
138. Holst, B.; Lang, M.; Brandt, E.; Bach, A.; Howard, A.; Frimurer, T.M.; Beck-Sickinger, A.; Schwartz, T.W., Ghrelin receptor inverse agonists: identification of an active peptide core and its interaction epitopes on the receptor. Mol Pharmacol, 2006, 70, (3), 936-946.
139. Sun, Y.; Butte, N.F.; Garcia, J.M.; Smith, R.G., Characterization of adult ghrelin and ghrelin receptor knockout mice under positive and negative energy balance. Endocrinology, 2008, 149, (2), 843-850.
140. Asakawa, A.; Inui, A.; Kaga, T.; Katsuura, G.; Fujimiya, M.; Fujino, M.A.; Kasuga, M., Antagonism of ghrelin receptor reduces food intake and body weight gain in mice. Gut, 2003, 52, (7), 947-952.
141. Helmling, S.; Maasch, C.; Eulberg, D.; Buchner, K.; Schroder, W.; Lange, C.; Vonhoff, S.; Wlotzka, B.; Tschop, M.H.; Rosewicz, S.; Klussmann, S., Inhibition of ghrelin action in vitro and in vivo by an RNA-Spiegelmer. Proc Natl Acad Sci U S A, 2004, 101, (36), 13174-13179.
142. Barnett, B.P.; Hwang, Y.; Taylor, M.S.; Kirchner, H.; Pfluger, P.T.; Bernard, V.; Lin, Y.Y.; Bowers, E.M.; Mukherjee, C.; Song, W.J.; Longo, P.A.; Leahy, D.J.; Hussain, M.A.; Tschop, M.H.; Boeke, J.D.; Cole, P.A., Glucose and weight control in mice with a designed ghrelin O-acyltransferase inhibitor. Science, 2010, 330, (6011), 1689-1692.
143. Esler, W.P.; Rudolph, J.; Claus, T.H.; Tang, W.; Barucci, N.; Brown, S.E.; Bullock, W.; Daly, M.; Decarr, L.; Li, Y.; Milardo, L.; Molstad, D.; Zhu, J.; Gardell, S.J.; Livingston, J.N.; Sweet, L.J., Small-molecule ghrelin receptor antagonists improve glucose tolerance, suppress appetite, and promote weight loss. Endocrinology, 2007, 148, (11), 5175-5185.