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The Health Agenda, Volume 2. Issue 1. January, 2014 REVIEW ARTICLE Effect of ghrelin on regulation of growth hormone release: A review Authors: Mahalaqua Nazli Khatib, Shivaji Chalak, Arunita Bagga, Tripti Waghmare Corresponding author: Dr. Mahalaqua Nazli Khatib Associate Professor, Dept. of Physiology J N Medical College, Datta Meghe Institute of Medical Sciences Sawangi (Meghe), Wardha, Maharashtra - 442004 Mail ID: [email protected] ABSTRACT Background: The occurrence of ghrelin indicates that GH release from the pituitary may be regulated not only by hypothalamic growth hormone releasing hormone (GHRH), but also by ghrelin, a natural endogenous ligand of the growth hormone secretagogue receptor (GHSR). Objective: To review the role of ghrelin as a stimulant for the secretion of GH and GHRH. Methodology: We searched the following electronic databases: The Cochrane Library, MEDLINE, PubMed, Science Citation Index, BIOSIS, EMBASE, and CINAHL. The references of all identified studies were inspected for further randomized controlled trials. No language restrictions were applied. Results: The ghrelin receptor growth hormone secretagogue receptor-1 (GHSR-1) is found in several neuronal subtypes in the arcuate nucleus. In the presence of SS, the percent increase in GH released with human ghrelin plus GHRH was greater than that by either human ghrelin or GHRH alone. Conclusion: Ghrelin increases GH release and can be used as an adjunctive treatment. Reported adverse events were infrequent, mild, and transient. Future trials should report clinical as well as physiological outcomes. The role of ghrelin in the regulation of GH and its clinical implications needs further assessment. Key words: Bioactive peptide, Ghrelin, Growth hormone, Secretagogue receptor INTRODUCTION Ghrelin is produced primarily by the rare neuroendocrine cells of the gastric fundus. Lower concentrations have also been reported in the remainder of the bowel including the colon. Ghrelin positive cells are positioned close to the capillaries and have no contact with the lumen of the oxyntic gland, indicating that secretion occurs into the plasma and not into the intestinal tract. The pancreas is a major source of ghrelin in the perinatal period, whereas gastric production progressively increases after birth.(1,2) In the central nervous system, neuronal cell groups release ghrelin in a synaptic transmission. It acts in the arcuate nucleus of the hypothalamus and in somatotrophs in the pituitary to release growth hormone. Also, pituitary, heart, kidney, endocrine pancreas, gonads, lungs, and lymphocytes all express ghrelin in low amounts. The occurrence of ghrelin in both rat and human indicates that GH release from the pituitary may be regulated not only by hypothalamic GHRH, but also by ghrelin.(3) The Health Agenda, Online ISSN No: 2320-3749 In collaboration with GHRH and somatostatin, ghrelin may well be the third peptidergic factor involved in GH regulation. Ghrelin exerts pleiotropic actions, consistent with the widespread distribution of ghrelin and GHS-R expression in central and peripheral tissues. Ghrelin has been shown to exhibit a range of actions on cardiovascular, gastrointestinal, and pancreatic functions, as well as lipogenic and glucogenic actions.(4) It is suggested that the main physiological function of ghrelin is to stimulate growth hormone release from the pituitary and increase food intake.(5) Active ghrelin acts as an amplifier of GHRH, the primary agonist of GH secretion. Ghrelin is also acutely influenced by diet composition. Studies examining effects of onetime test meals have reported that carbohydrate induces the most potent ghrelin suppression, whereas lipids have the weakest effect on suppression. In fact, ghrelin secretion is increased by fasting, whereas, it is decreased by glucose load as well as during euglycemic clamp, but not after arginine or free fatty acid load in normal subjects. Page | 4 Khatib MN, Chalak S, Bagga A, Waghmare T: Effect of ghrelin on growth hormone In physiological conditions, however, the most remarkable inhibitory input on ghrelin secretion is represented by somatostatin as well as by its natural analog cortistatin that concomitantly reduce beta-cell secretion.(6-9) This evidence indicates that endocrine pancreas plays a role in modulating ghrelin secretion. The objective of the study is to review the role of Ghrelin as a stimulant for the secretion of GH and GHRH. METHODOLOGY We searched the following electronic databases: The Cochrane Library, MEDLINE, PubMed, Science Citation Index, BIOSIS, EMBASE, and CINAHL. The references of all identified studies were inspected for further randomized controlled trials. No language restrictions were applied. Searching other resources: A manual search was performed for all medical journals. Experts, authors and manufacturers were contacted to seek clarifications and asked to contribute via published and unpublished material. Selection of studies: Two reviewers independently screened the title and abstracts from searches on electronic databases to identify those articles relevant to this review. Full articles were retrieved for further assessment. All full text articles were read independently by two reviewers to make a decision on inclusion. Disagreements were resolved by discussion and by seeking the opinion of the third reviewer. Additional unpublished data were also obtained by contacting the authors of the papers. MOLECULAR FORMS OF GHRELIN The major active products of the ghrelin gene in the stomach of rats, mice and humans are 28-amino acid peptides acylated at the serine-3 position with an n-octanoyl group (C8:0-ghrelin), called simply ghrelin.(6) In mammals, two major forms of ghrelin are found in circulation, octanoylated ghrelin at Ser-3 and des-acyl ghrelin. Kojima discovered the first natural hormone in which the third amino acid of ghrelin was a serine residue that was esterified with n-octanoic acid, an eight-carbon fatty acid, attached to serine-3 in an O-acyl linkage.(7) This peculiar posttranslational modification is capable of increasing its lipophilicity. The octanoate moiety is essential for the function of ghrelin in releasing growth hormone from pituitary cells and removing the octanoate blocked ghrelin's ability to bind to or activate its receptor. Like ghrelin itself, the octanoate modification is conserved throughout the vertebrate lineage.(8,9) The first seven amino acids of N-terminal region ‘active core’ in all vertebrate; ghrelins display high sequence homology, suggesting that the biological actions of ghrelin are highly conserved across vertebrates. However, recent studies have revealed that the ghrelin gene can generate a variety of bioactive molecules besides ghrelin. These include acyl forms of ghrelin other than C8:0-ghrelin (i.e., n-decanoyl ghrelin or n-decenoyl ghrelin), des-acyl ghrelin, obestatin and ghrelin-associated peptides originated from the ghrelin gene.(10) In the rat stomach, a second type of ghrelin peptide with a C8:0-modification has been identified as the desGln14-form of “ghrelin” (C8:0-des-Gln14-ghrelin), a 27-amino acid peptide hormone.(11) Another ligand, a 27-amino-acid peptide named des-Gln14ghrelin, the sequence of which is identical to ghrelin except for one glutamine. Therefore, there is evidence that GH release is regulated by two gastric peptides secreted by endocrine cells, even if brain ghrelin immunoreactive neurons have also been localized in the hypothalamic arcuate nucleus.(12) Acyl ghrelins bind to the growth hormone secretagogue receptor (GHS-R) similar to C8:0ghrelin, and exert biological effects by stimulating this receptor. In this respect, acyl ghrelins are clearly distinguished from other ghrelin-family peptides, such as des-acyl ghrelin or other ghrelinassociated peptides none of which can interact with and directly stimulate the GHS-R. The des-acyl ghrelin also exists at significant levels in the stomachs of rats, mice, humans(2,9, 13-15) as well as other mammalian and nonmammalian species; where the ratio of des-acyl Page | 5 The Health Agenda, Volume 2. Issue 1. January, 2014 ghrelin to acyl ghrelins (measured by the C8ghrelin RIA) is approximately 1:2 to 2:1. Administration of acylated ghrelin to rat pups directly does not affect weight gain. In contrast, administration of ghrelin to pregnant or lactating rats results in greater fetal weight and postnatal weight gain, suggesting that maternal ghrelin may stimulate perinatal growth.(16) FORMATION OF GHRELIN Ghrelin is primarily synthesized as a preprohormone consisting of 117 amino acids. Cleavage of preproghrelin results in two mature ghrelin molecules, a 28 amino acid form (C-terminal Arg) or a 27 amino acid form (C-terminal Pro). Ghrelin represents the NH2terminal 28-amino acids of proghrelin, which is produced from preproghrelin by cleavage of the signal peptide.(17) MECHANISM OF ACTION Ghrelin is produced by stomach and activated by post-translational acylation before being transported into blood stream. It can then cross the blood-brain barrier,(18) where it binds to the growth hormone secretagogue receptor 1a (GHSR1a, or ghrelin receptor). The ghrelin receptor is found in several neuronal subtypes in the arcuate nucleus.(14) This peptide binds to the GH secretagogue receptor 1a, a G protein-coupled receptor located in pituitary gland, hypothalamus, and several peripheral tissues.(19-22) Ghrelin targets the arcuate nucleus, from where growth hormone releasing hormone (GHRH) neurones trigger GH secretion. Ghrelin not only stimulates the growth hormone (GH) axis(14) but also induces feeding and modifies body energy consumption, as well as modulating the gonadotropic axis.(5) Circulating ghrelin levels are regulated through acylation of preproghrelin by GOAT and depend on the presence of luminal medium-chain fatty acids (MCFA).(8) Ghrelin increases GH release. GH release from the pituitary is inhibited by IGF-I negative feedback.(10) LEVELS OF GHRELIN In humans and rodents plasma ghrelin concentrations rise dramatically before meals and decline precipitously after food ingestion. The results of the Arvat’s study show that in humans, ghrelin possesses a strong stimulatory effect on GH secretion, releasing more GH than GHRH and even than a non-natural GHS. The effect of ghrelin is, however, not fully specific for GH. On molar basis, the present results suggest that ghrelin is more potent in releasing GH than synthetic nonnatural GHS. GH response to ghrelin is not modified by the co-administration of HEX indicating that somatotroph responsiveness to ghrelin is reproducible; this property could have clinical implication when ghrelin is considered as a provocative test of GH secretion.(13) SINGLE EFFECT AND COMBINED EFFECT Yamazaki (2002) used a peri-fusion system to examine the single effect and combined effects of ghrelin with growth hormone-releasing hormone (GHRH) and somatostatin on GH secretion from rat anterior pituitary cells. DOSE Ghrelin stimulated GH secretion from the rat anterior pituitary cells in a dose-dependent manner. The intra-arterial injection of 1 microg/kg BW of rat ghrelin in ovariectomized goats failed to stimulate GH release, however, a dosage of 3 microg/kg BW significantly increased plasma GH concentrations (p<0.05).(14) GHRELIN AND GHRH Ghrelin caused weaker GH secretion than that caused by GHRH, and that co-stimulation with GHRH had no additive or synergistic effect on GH secretion, suggesting that ghrelin indirectly affects coordinated GH release from pituitary gland, as found in vivo. When human ghrelin and GHRH were added together, the release of GH induced by both peptides was significantly greater than that by human ghrelin alone (p<0.05), and tended to be greater than that by GHRH alone.(5) Somatostatin significantly blunted GH release induced by human ghrelin and GHRH. In the presence of SS, the percent increase in GH released with human ghrelin plus GHRH was greater than that by either human ghrelin or GHRH alone (p<0.05). Human ghrelin and GHRH Page | 6 Khatib MN, Chalak S, Bagga A, Waghmare T: Effect of ghrelin on growth hormone have a synergistical effect on GH secretion agrees with the well-known synergism between nonnatural GHS and GHRH. As previously hypothesized, based on the effect of non-natural GHS, the synergistical interaction between ghrelin and GHRH indicates that these peptides act, at least partially, via different mechanisms.(19) HUMAN AND RAT GHRELIN Rat and mouse ghrelin are identical and differ from human ghrelin by only two amino acids (Arg11-Val12 replacing Lys11-Ala12). To clarify the direct effects of ghrelin on growth hormone (GH) release from anterior pituitary cells in cattle, GH-releasing effects of human ghrelin and rat ghrelin on bovine anterior pituitary cells were compared with those of GH-releasing hormone (GHRH) in vitro.(14) The secretory response to 3 microg/kg BW of rat ghrelin was weaker than that of growth hormone-releasing hormone (GHRH) (0.25 microg/kg BW) (p<0.05).(17) REFERENCES 1. 2. 3. Chanoine JP, De Waele K, Walia P. Ghrelin and the growth hormone secretagogue receptor in growth and development. Int J Obes 2009;33(Supp1):S48-52. 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):656-60. Kojima M, Hosoda H, Matsuo H, Kangawa K. Ghrelin: Discovery of the natural endogenous ligand for the growth hormone secretagogue receptor. Trends Endocrinol Metab 2001;12(3):118-22. 4. Meyer RM, Burgos-Robles A, Liu E, Correia S, Goosens KA. A ghrelin–growth hormone axis drives stress-induced vulnerability to enhanced fear. Molecular Psychiatry 2013. 5. Osterstock G, Escobar P, Mitutsova V, GoutyColomer L-A, Fontanaud P. Ghrelin stimulation of growth hormone-releasing hormone neurons is direct in the arcuate nucleus. PLoS ONE 2010;5(2):e9159. ANIMAL STUDIES Little is known about its GH-releasing activity and endocrine effects in domestic animals. To clarify the effect of ghrelin on GH secretion in vivo in ruminants, plasma GH responses to intra-arterial and intra-hypothalamic injections of rat ghrelin were examined in goats and cattle and the results show that ghrelin stimulates GH release in ruminants. An infusion of 10 nmol of ghrelin into the medial basal hypothalamus (arcuate nucleus) significantly stimulated the release of GH in male calves (p<0.05).(15) CONCLUSION Ghrelin indirectly affects co-ordinated GH release from pituitary gland and can be used as an adjunctive treatment. The role of ghrelin in the regulation of GH and its clinical implication needs further assessment. 6. Tena-Sempere M. Ghrelin and reproduction: ghrelin as novel regulator of the gonadotropic axis. Vitam Horm 2008;77:285-300. 7. Ghigo E, Broglio F, Arvat E, Maccario M, Papotti M, Muccioli G. Ghrelin: more than a natural GH secretagogue and/or an orexigenic factor. Clin Endocrinol 2005; 62(1):1-17. 8. Kojima K, Kangawa K. Structure and function of Ghrelin. In Orphan G Protein-coupled receptors and novel neuropeptides. Civelli O and Zhou QY, Eds., Springer, Berlin, Germany 2008; 90-115. 9. Nishi Y, Yoh J, Hiejima H, Kojima M. Structures and molecular forms of the ghrelinfamily peptides. Peptides: 2011;32(11), 217582. 10. Schwandt SE, Peddu SC, Riley LG. Differential roles for octanoylated and decanoylated ghrelins in regulating appetite and metabolism. International Journal of Peptides 2010 (2010), ID 275804. Available: http://dx.doi.org/10.1155/2010/275804 Page | 7 The Health Agenda, Volume 2. Issue 1. January, 2014 11. Li X, He J, Hu W and Yin Z. The essential role of endogenous ghrelin in growth hormone expression during zebrafish adenohypophysis development. Endocrinology 2009;150(6): 2767-74. 12. Kaiya H, Miyazato M, Kangawa K, Peter RE, Unniappan S. Ghrelin: a multifunctional hormone in non-mammalian vertebrates. Comp Biochem and Physiol 2008;149(2): 109-28. 13. Hosoda H, Kojima M, Matsuo H, Kangawa K. Purification and characterization of rat desGln14-Ghrelin, a second endogenous ligand for the growth hormone secretagogue receptor. J Biol Chem. 2000; 275(29):219952000. 14. 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(3), 909-13. 15. Kojima M, Kangawa K. Ghrelin: structure and function. Physiol Rev 2005; 85(2):495-522. 16. Perboni S, Inui A. Appetite and gastrointestinal motility: role of ghrelinfamily peptides. Clin Nutr. 2010; 29(2):22734. 17. Soares JB, Leite-Moreira AF. Ghrelin, des-acyl ghrelin and obestatin: three pieces of the same puzzle. Peptides. 2008;29(&):1255-70. 18. Hosoda H, Kojima M, Mizushima T, Shimizu S, Kangawa K. Structural divergence of human ghrelin. Identification of multiple ghrelinderived molecules produced by posttranslational processing. J Biol Chem 2003; 278(1):64-70. 19. Nass RM, Gaylinn BD, Rogol AD, Thorner MO. Ghrelin and growth hormone: story in reverse. Proc Natl Acad Sci 2010; 107(19): 8501-2. 20. Arvat E, Lidia D, Broglio F, Benso A, Gottero C, Papotti M et al. Endocrine activities of ghrelin, a natural growth hormone secretagogue (GHS), in humans: comparison and interactions with hexarelin, a nonnatural peptidyl GHS, and GH-releasing hormone. J Clin Endocrinol Metab. 2001;86(3):1169-74. 21. Yamazaki M, Nakamura K, Kobayashi H, Matsubara M, Hayashi Y, Kangawa K. Regulational effect of ghrelin on growth hormone secretion from perifused rat anterior pituitary cells. J Neuroendocrinol. 2002; 14(2):156-62. 22. Hashizume T, Horiuchi M, Tate N, Nonaka S, Kojima M, Hosoda H, Kangawa K. Effects of ghrelin on growth hormone secretion from cultured adenohypophysial cells in cattle. Endocr J. 2003; 50(3):289-95. Particulars of Contributors: 1. 2. 3. 4. Dr. Mahalaqua Nazli Khatib, Associate Professor Dr. Shivaji Chalak, Associate Professor Dr. Arunita Bagga, Assistant Professor Dr. Tripti Waghmare, Professor Dept. of Physiology J N Medical College Datta Meghe Institute of Medical Sciences Sawangi (Meghe), Wardha, Maharashtra Source of funding: Nil Conflict of interest: None Date of Submission: 10 November, 2013 Date of Acceptance: 25 November, 2013 Date of Publishing: 5 January, 2014 Page | 8