THE GHRELIN SYSTEM; BEYOND THE ROLE IN ENERGY HOMEOSTASIS

Ljiljana Šaranac, Zoran Gucev

DOI Number
10.22190/FUMB170118002S
First page
33
Last page
38

Abstract


The fascinating story of ghrelin started more than 30 years ago with the discovery of synthetic (non-natural) growth hormone (GH) releasing peptides. Scientists were searching for a novel peptide, ligand of orphan GH secretagogue receptor. The discovery of ghrelin is a typical example of reverse pharmacology. The new peptide quickly attracted a lot of attention by its pleiotropic nature, and provoked a burst of new enthusiasm among scientists and clinicians. Ghrelin is mainly produced in the stomach from a distinct group of endocrine cells located within the gastric oxyntic mucosa. It acts as hunger signal and long-term body weight regulator. But, ghrelin is much more than just a natural orexigenic factor and GH secretagogue. It exerts major peripheral endocrine and non-endocrine actions, and it has a role in learning and memory, glucose homeostasis, immunity, cardio protection, fertility and addiction. Exploring the actions of ghrelin and ghrelin agonists and receptor antagonists or reverse agonists could establish new treatment options for so far incurable diseases.

Keywords

Ghrelin, energy homeostasis, obesity, anorexia nervosa, ghrelin application, sepsis

Full Text:

PDF

References


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.

Kojima M, Kingawa K. Ghrelin structure and function. Physiol Rev 2005; 85:405-522.

Sato T, Nakamura Y, Shimura Y, Ohgusu H, Kangawa K, Kojima M. Structure, regulation and function of ghrelin. J Biochem 2012; 151(2):119-128.

Wren A. Gut and hormones and obesity. Fron Horm Res 2008; 36:165-181.

Kojima M, Kangawa K. Ghrelin discovery: a decade after. In: The ghrelin system. Benso A, Casaneuva FF, Ghigo E, Granata A Eds Endocr Dev Basel, Karger 2013; 55:1-4.

Reimer MK, Pacini G, Ahren B. Dose dependent inhibition by ghrelin of insulin secretion in the mouse. Endocrinology 2003; 144:916-921.

Tong J, Prigeon RI, Davis HW, Bidlingmaier M, Kahn SE, Cumming DE, Tschop MH, D’Alessio D. Ghrelin suppresses glucose-stimulated insulin secretion and deteriorates glucose tolerance in healthy humans. Diabetes 2010; 59: 2145-2151

Albararan-Zeckler R, Smith R. The ghrelin receptors (GHS-R1a and GHS-R1b). In: Benso A, Casaneuva FF, Ghigo E, Granata A (eds) The ghrelin system. Endocr Dev Basel: Karger 2013; 55:5-15.

Inui A. Ghrelin: an orexigenic and somatotrophic signal from the stomach. Nat Rev Neurosci 2001; 2:551-560.

Jeffery PL, McGuckin MA, Linden SK. Endocrine impact of Helicobacter pylori: focus on ghrelin and ghrelin o-acyltransferaze. World J Gastroenterol 2011; 17(10):1249-1260.

Ghigo E, Arvat E, Broglio F, Giordano R, Gianotti L, Muccioli G, Papotti M, Graziani A, Bisi G, Deghenghi R, Camanni F: Endocrine and non-endocrine activities of growth hormone secretagogues in humans. Horm Res 1999: 51(Suppl 3):9-15.

Gokcel A, Yuksel Gumurdulu1 Y, Fazilet Kayaselcuk F, Ender Serin E, Birol Ozer B, Kursad Ozsahin A, Guvener N. Helicobacter pylori has no effect on plasma ghrelin levels. Eur J Endocrinol 2003; 148:423-426.

Tschop M, Smiley D, Heiman M. Ghrelin induces adiposity in rodents. Nature 2000; 407:908-913.

Boltin D, Niv Y. Ghrelin, Helicobacter pylori and body mass: is there association? Reviews 2012; 14: 130-132.

Andrich D, Cianflone K, Comtois AS, St-Pierre D. The endocrine effects of acylated and des-acylated ghrelin. Research and Reports in Endocrine disorders 2012; 2:31-40.

Iniguez G, Roman R, Youlton R, Cassorla F, Mericq V. Ghrelin plasma levels in patients with idiopathic short stature. Horm Res Pediatr 2011; 75:94-100.

Tena-Sempere M. Ghrelin, the gonadal axis and the onset of puberty. In: Benso A, Casaneuva FF, Ghigo E, Granata A (eds) The ghrelin system. Endocr Dev. Basel, Karger 2013; 25:69-82.

Benso A, Calvi E, Gramaglia E, Olivetti I, Tomelini M, Ghigo E, Broglio F. Other than growth hormone neuroendocrine actions of ghrelin. In: Benso A, Casaneuva FF, Ghigo E, Granata A (eds) The ghrelin system. Endocr Dev. Basel, Karger 2013; 25:59-68.

Thompson NM, Gill DA, Davies R, Loveridge N, Houston PA, Robinson IC, Wells T. Ghrelin and des-octanoyl ghrelinpromote adipogenesis directy in vivo by mechanism independent of the type 1a growth hormone secretagogue receptor. Endocrinology 2004; 145:234-242.

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 secretagogue receptor. Eur J Pharmacol 2004; 498:27-35.

Chanoin JP. Ghrelin in growth and development. Horm Res 2005; 63:129–138.

Wali P, King J, He Z, Tonb D, Horvath K. Ghrelin and obestatin level in children with failure to thrive and obesity. J Pediatr Gastroenterol Nutr 2014; 58:376-381.

Shen C, Yu T, Tang ZH, Wu KM. Changes in ghrelin and obestatin levels before and after a meal in children with simple obesity and anorexia. Horm Res Pediatr 2013; 79(6):341-6.

Arrigo T, Gitto E, Ferraù V, Munafò C, Alibrandi A, Marseglia GL, Salpietro A,Miraglia Del Giudice M, Leonardi S, Ciprandi G, Salpietro C. Effect of weight reduction on leptin, total ghrelin and obestatin concentrations in prepubertal children. J Biol Regul Homeost Agents. 2012; 26(1 Suppl):S95-103.

Feigerlová E1, Diene G, Conte-Auriol F, Molinas C, Gennero I, Salles JP, Arnaud C, Tauber M. Hyperghrelinemia precedes obesity in Prader-Willi syndrome. J Clin Endocrinol Metab. 2008;93: 2800-2805.

Wang W, Bansal Shweta B, Falk S, Ljubanovic D, Schrier R. Ghrelin protects mice against endotoxemia- induced acute kidney injury. Am J Physiol Renal Physiol 2009; 297: F1032-F1037.

Wu R, Dong M, Zhou X, Cui H, Simons H, Wang P. Ghrelin improvestissue perfusion in severe sepsis via downregulation of endothelin-1. Cardiovascular Res 2005; 68:318-326.

Chorny A, Anderson P, Gonzales-Rey E, Delgado M. Ghrelin protects against experimental sepsis by inhibiting High-mobility group box 1 release and by killing bacteria. J Immunol 2008; 180:8369-8377.

Yang WL, Ma G, Zhou M, Aziz M, Yen HT, Mavropoulos S, Ojamaa K, Wang P. Combined administration of human ghrelin and human growth hormone attenuates organ injury and improves survival in aged septic rats. Mol Med 2016; 22:

-135. doi: 10.2119/molmed.2015.00255.

Inoue S, Suzuki K, Komori Y, Morishita Y, Suzuki-Utsunomiya K, Hozumi K, Inokuchi S, Sato T. Persistent inflammation and T cell exhaustion in severe sepsis in the elderly. Crit Care 2014; 18(3):R130. doi: 10.1186/cc13941.

Jacob A, Rajan D, Pathickal B, Balouch I, Hartman A, Wu R, Zhou M, Wang P. The inhibitory effect of ghrelin on sepsis-induced inflammation is mediated by the MAPK phosphatase-1. Int J Mol Med 2010 ;25:159-164.

Cheyuo C, Jacob A, Wang P. Ghrelin-mediated sympathoinhibition and suppression of inflammationin sepsis. Am J Physiol Endocrinol Metab 2012; 302:E265–E272.

Menzies J, Skibicka K, Leng Gareth. Ghrelin, reward and motivation. In: Benso A, Casaneuva FF, Ghigo E, Granata A (eds) The ghrelin system. Endocr Dev. Basel, Karger 2013; 25: 101-111.

Schellekens H, Finger BC, Dinan TG, Cryan JF. Ghrelin signalling and obesity: at the interface of stress, mood and food reward. Pharmacol Ther 2012; 135:316-326.

Schellekens H, Dinan TG, Cryan JF. Taking two to tango: a role for ghrelin receptor heterodimerization in stress and reward. Front Neurosci 2013; 7:1-18.

Depoortere I. Targeting the ghrelin receptor to regulate food intake. Regul Pept 2009; 91: 285-323.

Engel JA, Nylander I, Jerlhag E. A ghrelin receptor (GHS-R1A) antagonist attenuates the rewarding properties of morphine and increases opioid peptide levels in reward areas in mice. Eur Neuropsychopharmacol 2015; 25:2364-2371.

Nagaya N, Kojima M, Uematsu M, Yamagushi M, Hosoda H, Oya H, Hayashi Y, Kangawa K. Hemodynamic and hormonal effects of human ghrelin in healthy volunteers. Am J Physiol Regul Integr Comp Physiol 2001; 280:R1483-R1487.

Li WG, Gavrila D, Liu X, Wang L, Gunnlaugsson S, Stoll LL, McCormick ML, Sigmund CD, Tang C, Weintraub NL. Ghrelin inhibits proinflammatory responses and nuclear factor-kappaB activation in human endothelial cells. Circulation 2004; 109: 2221-2226.

Locatelli V, Rossoni G, Schweeiger F, Torsello A, De Gennaro Colonna V, Bernarreggi M, Deghenghi R, Muller EE, Berti F. Growth hormone independent cardioprotective effects of hexarelin in the rat. Endocrinology 1999; 140:4024-4031.

Nagaya N1, Uematsu M, Kojima M, Ikeda Y, Yoshihara F, Shimizu W, Hosoda H, Hirota Y, Ishida H, Mori H, Kangawa K. Chronic administration of ghrelin improves left ventricular dysfunction and atenuates development of cardiac cachexia in rats with heart failure. Circulation 2001: 104(12):1430-1435.

Isgaard J. Ghrelin and the cardiovascular system. In: Benso A, Casaneuva FF, Ghigo E, Granata A (eds) The ghrelin system. Endocr Dev. Basel, Karger 2013; 25:83-90.

Palus S, von Haehling S, Doehner W, Datta R, Zhang J, Dong JZ, Culler MD, Anker SD, Springer J. Effect of application route of the ghrelin analog BIM-28131 (RM-131) on body weight and body composition in a rat heart failure model. Int J Cardiol 2013; 168:2369-2374.

Saranac L, Bjelakovic B, Stamenkovic H, Kamenov B. Orexitropic signaling proteins in obese children. The Scientific World Journal 2007; 7:1263-1271.

Allas S, Abribat T. Clinical Perspectives for ghrelin-derived therapeutic products. In: Benso A, Casaneuva FF, Ghigo E, Granata A (eds) The ghrelin system. Endocr Dev. Basel, Karger 2013; 25:157-166

Drazen DL, Woods SC. Peripheral signals in the control of satiety and hunger. Curr Opin Clin Nutr Metab Care 2003; 6: 621-629.

Garcia JM, Boccia RV, Graham CD, Yan Y, Duus EM, Allen S, Friend J. Anamorelin for patients with cancer cachexia: an integrated analysis of two phase 2, randomised, placebo-controlled, double-blind trials. Lancet Oncol 2015; 16:108-116.

Bai Y, Hu Y, Zhao Y, Yu X, Xu J, Hua Z, Zhao Z. Anamorelin for cancer anorexia-cachexia syndrome: a systematic review and meta-analysis. Support Care Cancer 2017, Jan 10. doi: 10.1007/s00520-016-3560-0. [Epub ahead of print]

Ukkola O. Peripheral regulation of food intake: new insights. J Endocrinol Investig 2004; 27:96-98.

Haruta I, Fuku Y, Kinoshita K, Yoneda K, Morinaga A, Amitani M, Amitani H, Asakawa A, Sugawara H, Takeda Y, Bowers CY, Inui A. One-year intranasal application of growth hormone releasing peptide-2 improves body weight and hypoglycemia in a severely emaciated anorexia nervosa patient. J Cachexia Sarcopenia Muscle 2015; 6:237-241.

Tseng PH, Wu MS, Kao JH. Recent advances in clinical application of gut hormones. J Formos Med Assoc 2010; 109: 859-861.




DOI: https://doi.org/10.22190/FUMB170118002S

Refbacks

  • There are currently no refbacks.


ISSN 0354-2017 (Print)

ISSN 2406-0526  (Online)