Download Effect of ghrelin on regulation of growth hormone release: A review

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.
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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
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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
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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
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3.
Chanoine JP, De Waele K, Walia P. Ghrelin and
the growth hormone secretagogue receptor in
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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
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Meyer RM, Burgos-Robles A, Liu E, Correia S,
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Osterstock G, Escobar P, Mitutsova V, GoutyColomer L-A, Fontanaud P. Ghrelin
stimulation of growth hormone-releasing
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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
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7.
Ghigo E, Broglio F, Arvat E, Maccario M,
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8.
Kojima K, Kangawa K. Structure and function
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10. Schwandt SE, Peddu SC, Riley LG. Differential
roles for octanoylated and decanoylated
ghrelins in regulating
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11. Li X, He J, Hu W and Yin Z. The essential role of
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expression during zebrafish adenohypophysis
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12. Kaiya H, Miyazato M, Kangawa K, Peter RE,
Unniappan S. Ghrelin: a multifunctional
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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
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279(3), 909-13.
15. Kojima M, Kangawa K. Ghrelin: structure and
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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,
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19. Nass RM, Gaylinn BD, Rogol AD, Thorner MO.
Ghrelin and growth hormone: story in
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C, Papotti M et al. Endocrine activities of
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peptidyl GHS, and GH-releasing hormone. J
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21. Yamazaki
M, Nakamura
K, Kobayashi
H, Matsubara M, Hayashi Y, Kangawa K.
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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
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