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Original Paper
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Acta Biochim Biophys Sin 2009, 41: 188–197 |
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doi: 10.1093/abbs/gmp001. |
Ghrelin
fluctuation, what determines its production?
Xuefeng Yin1, Yin Li1,
Geyang Xu1, Wenjiao An1, and Weizhen Zhang1,2*
1Department of Physiology and Pathophysiology,
2Department of Surgery,
*Correspondence address. Tel: t86-10-82802183;
Fax: t86-10-82802183; E-mail: [email protected]
Ghrelin, a 28 amino acid gut brain peptide,
acts as an endogenous ligand for its receptor, the growth hormone secretagogue
receptor, to exercise a variety of functions ranging from stimulation of growth
hormone secretion, regulation of appetite and energy metabolism, and cell
protection to modulation of inflammation. This review summarizes the advance in
the regulation of ghrelin expression and secretion. We introduce the structure
of ghrelin promoter, the processing and modification of ghrelin precursor, and
the regulation mechanism in these processes. Then we discuss factors found to
be important in the regulation of ghrelin production, including nutrients,
hormones, and autonomic nervous system. Finally, we outline the alteration in
the level of ghrelin in certain physiological and pathological status.
Keywords ghrelin; regulation; diet;
secretion; biosynthesis
Received: September 2, 2008 Accepted:
December 9, 2008
Introduction
Ghrelin is an acyl-peptide composed of 28
amino acids. It is synthesized mainly by X/A-like cells in the gastric mucosa,
but also found in hypothalamus, pituitary gland, hippocampus, brain cortex,
adrenal gland, intestine, pancreas, and many other human tissues [1–3]. Ghrelin has a unique structure, with an N-octanoyl
group covalently linked to the hydroxyl group of its serine 3 residue. This
octanoylation is necessary for ghrelin to bind with its receptor, the growth
hormone secretagogue receptor (GHS-R) [4]. Through the mediation of this seven
transmembrane G-protein-coupled receptor, ghrelin exerts neuroendocrine effects
of eliciting growth hormone release, regulating appetite and energy metabolism,
and carries many other functions in a variety of tissues and organs such as
gastroenteropancreatic system, cardiovascular system [5], reproduction system
[6], and immune system [7]. Although numerous results about the function of
ghrelin in physiological and pathological conditions have been reported,
emerging evidences suggest that the regulation of ghrelin expression and
secretion is complicated yet precise. Regulation of ghrelin concentration may
occur at different levels ranging from transcription, posttranscription,
translation, post-translation modification to secretion, suggesting the
remarkable complexity of its regulation. This review summarizes the recent
progress in the regulation of ghrelin expression and secretion, explores the
possible mechanism involved, and introduces factors which are important for its
regulation such as nutrients, hormones, autonomic nervous system, and lastly
discusses altered level of ghrelin in certain physiological and pathological
status.
Transcriptional Regulation of Ghrelin
As shown in Fig 1, ghrelin gene spans 5 kb of
the genomic DNA on chromosome 3p25–26,
consisting of four introns and five exons, including a non-coding exon 1.
Ghrelin gene encodes a pre-proghrelin composed of 117 amino acid residues,
which can be further processed into acyl ghrelin, des-acyl ghrelin, and
obestatin. The 5'-upstream regulation region of the ghrelin gene consists of
binding sites of several transcriptional factors such as upstream stimulatory
factor21/22 [8], activator proten-1, CCAAT enhancer binding proteins, and cAMP
response element binding protein [9], indicating that these transcription
factors may regulate ghrelin expression. However, evidence for the direct
regulation of these transcriptional factors on ghrelin gene expression is still
lacking. Recently, a report revised the structure of ghrelin gene,
demonstrating the presence of an additional novel exon, detecting several
ghrelin genederived mRNA splice variants, including transcripts which probably
encode C-ghrelin, obestatin or novel protein isoforms, and antisense non-coding
regulatory transcripts [10]. This study reveals that the ghrelin gene locus may
be far more complex than previously recognized and the transcription regulation
mechanism remains to be unraveled.
Post-translational Modification of Ghrelin
Precursor Protein
Ghrelin is the only protein currently known
to be octanoylated. This unique modification is necessary for ghrelin to bind
with its receptor, GHS-R
Nutrients Regulating Ghrelin Expression and
Secretion
Glucose markedly inhibits ghrelin secretion.
Oral infusion of glucose can decrease the plasma concentration of total ghrelin
30 min after ingestion in humans [27] and in rats [28]. Ingestion of crude
fiber has the similar effect with glucose [28]. Insulin-induced hypoglycemia
up-regulates ghrelin mRNA expression [29] and serum acyl ghrelin level [30] in
the stomach. It is, however, not clear whether glucose inhibits directly the
expression and secretion of ghrelin, or indirectly by the mediation of a yet to
be identified mechanism. Ingestion of either medium-chain fatty acids (n-octanoic
acid) or medium-chain triglycerides (glyceryl trioctanoate) increases the
stomach contents of acyl ghrelin without changing the total ghrelin in mouse
[31]. This study suggests that medium-chain fatty acids can be utilized
directly for the acyl modification of ghrelin as proposed by the author, but
may also indicate a decrease in ghrelin secretion and thus explain the
decrement in serum ghrelin level. Infusion of intralipid, a mixture of
long-chain triglycerides, decreases plasma total ghrelin in humans [32].
Intraduodenal administration of C12 dodecanoic acid decreases plasma ghrelin
significantly, whereas C10 decanoic acid has no effect [33]. The above
discoveries suggest that the effects of fatty acids and triglycerides on
ghrelin secretion are dependent on the length of their chain. Generally, lipid
ingestion leads to a smaller decline in ghrelin relative to the administration
of glucose or amino acids [34]. This observation may explain the weight gain
effect of high-fat dietary. Oral ingestion of a physiological dose of essential
amino acids leads to a continuous rise in serum ghrelin level in humans
[35,36], which unexpectedly contradicts with the inhibitory effect of protein
on ghrelin as discussed later in chapter 7. Insoluble dietary fiber ingestion
may influence ghrelin level as well [37].
Hormones Regulating Ghrelin Expression and
Secretion
Insulin
In rats, gastric artery perfusion of insulin
inhibits ghrelin release from isolated stomach tissue significantly [38].
Administration of insulin in central nervous system reduces serum total ghrelin
concentration [39]. Several observations in humans also indicate that insulin
may inhibit ghrelin secretion. Infusion of insulin significantly decreases
plasma ghrelin level while maintaining euglycemia [40,41].
Fasting plasma acyl ghrelin level is negatively related to insulin
concentration [30]. Total ghrelin level is also negatively related to
homeostasis model assessment insulin resistance index (HOMA-R) [42], and
positively related to insulin sensitivity [43]. GLP-1, a potent stimulator for
insulin secretion, has been reported to alleviate the pre-prandial rise of
ghrelin in humans [44]. This inhibitory effect of insulin may underlie the
suppression of glucose on ghrelin and the inverse relationship between body
weight and ghrelin level. It may also explain the low ghrelin level in patients
of type 2 diabetes mellitus as discussed in chapter 8. However, Toshinai et al.
[29] observed increment in ghrelin after insulin administration. This can be
explained as a result of severe hypoglycemia induced by rapid injection of high
dose of insulin. As suggested by Flanagan et al. [41], the influence of insulin
and glucose on ghrelin secretion is probably contradictory and independent.
Also, it is worth to note that insulin sensitivity, rather than insulin itself,
may play a more important role in the regulation of ghrelin [45]. It has been
reported that the insulin-induced hypoglycemia is independent of growth hormone
level [46]. But there is also a study showing that the negative correlation between
insulin and ghrelin disappears in patients with growth hormone disorder [30].
Therefore, it cannot be excluded that insulin interacts with growth hormone
axis to regulate ghrelin level.
Glucagon
Glucagon may contribute to the pre-prandial
surge of ghrelin as evidenced by the following observations. First, glucagon
receptor is present in endocrine cells in gastric mucosa [47]. Second, glucagon
concentration increases during fasting. Third, plasma acyl ghrelin
concentration rises transiently while des-acyl ghrelin increases persistently
after administration of glucagon in rats [47]. In addition, ghrelin released
from the rat stomach is augmented by glucagon perfusion [38]. Glucagon may
directly stimulate the gene transcription of ghrelin. The molecular mechanism
on how glucagon affects the expression of ghrelin remains to be explored. One
study reports that glucagon significantly elevates the activity of ghrelin gene
promoter in vitro [8] by the mediation of the second messenger cAMP. However,
it has also been reported that glucagon suppresses ghrelin secretion [48] by
the mediation of hypothalamus pituitary axis [49], because glucagon may
increase growth hormone and glucocorticoids which then inhibit ghrelin
secretion.
Growth hormone/insulin-like growth factor-1
(IGF-1) axis
Growth hormone therapy in growth hormone
deficient patients significantly decreases the serum acyl ghrelin concentration
[50]. Administration of growth hormone in cultured rat gastric tissue time
dependently inhibits total ghrelin secretion [51]. Administration of growth
hormone in rats significantly decreases the gastric mRNA content and plasma
ghrelin level, with no changes in gastric ghrelin level which may due to the
reduction in ghrelin releasing [52]. The above information supports the notion
that growth hormone exerts a negative feedback action on ghrelin production and
secretion. The concept that IGF-1 may promote ghrelin secretion is supported by
the following studies. Administration of recombinant human IGF
Somatostatin
Somatostatin probably inhibits ghrelin
synthesis directly, as shown by the observation that plasma acyl and total
ghrelin levels fall after the infusion of somatostatin or somatostatin analog
octreotide [55] and the presence of somatostatin receptor in rat stomach [56].
Somatostatin knockout mice display an increase in stomach ghrelin mRNA and
serum total ghrelin, but appear no alteration in hypothalamic and pituitary
ghrelin mRNA and serum acyl ghrelin concentration [57]. Since ghrelin increases
the level of somatostatin in plasma [58], the inhibitory effect of somatostatin
on ghrelin may be considered as a negative feedback modulation.
Leptin
Although some studies demonstrate that leptin
positively correlates with serum acyl ghrelin in normal weight woman [59] and
up-regulates ghrelin mRNA in mice stomach [29], it is generally agreed that
leptin inhibits ghrelin synthesis. Leptin is mainly synthesized and secreted by
adipose tissue [60]. Leptin concentration in obese is significantly higher than
normal, whereas ghrelin is lower [61]. Leptin
correlates with ghrelin in a complex pattern, which depends on the body weight
(normal or obesity) and insulin sensitivity or insulin concentration [59,62]. As shown by recent studies, ghrelin mRNA increases in
stomach during fasting whereas leptin and leptin mRNA decrease [63]. Leptin
dose-dependently inhibits ghrelin transcription in vitro [63] and decreases
ghrelin release from isolated rat stomach [38]. Central leptin gene therapy
decreases plasma leptin level and increases ghrelin level significantly in the
mouse fed with high-fat diet [64], indicating that leptin exerts its inhibition
on ghrelin secretion only in peripheral tissues. Thus, peripheral, especially
gastric leptin, probably represses ghrelin expression
through its receptor in gastric mucosa cells.
Estrogen
Many studies report that estrogen
up-regulates ghrelin level. Administration of estrogen elevates plasma total
ghrelin concentration in female patients with anorexia nervosa [53]. Ghrelin
mRNA level rises significantly after estrogen administration in cultured
stomach cells [65]. Estrogen has been well documented to regulate food intake
by modulating meal size and to stimulate growth hormone secretion. These
effects may be partially mediated through ghrelin. However, there also exist
discrepant results on the effect of estrogen on ghrelin. Estrogen replacement
therapy in post-menopausal women induces serum total [66] and acyl [67] ghrelin
secretion only to an insignificant extent, or even decreases [68] serum total
ghrelin level. Plasma acyl ghrelin concentration, ghrelin expressing cells and
ghrelin mRNA level in stomach, increases transiently after ovariectomy in the
female rats [69]. These contradictions may be attributed to the variation in
methods used for estrogen administration such as per oral or transdermal
administration [67,68], duration of estrogen administration, age [69] and
physiological status (such as obesity [68] vs. normal weight, post- or
pre-menopausal of experimental subjects), the outcome index measured (total
ghrelin or acyl ghrelin), and other experimental methods.
Autonomic Nervous System Regulating Ghrelin
Expression and Secretion
Autonomic nervous system, especially the
parasympathetic nerve, plays an important role in the regulation of ghrelin.
Excitation of the vagus nerve can stimulate ghrelin secretion. In rats and
humans, ghrelin level rises after administration of muscarinic agonists and
falls after administration of muscarinic antagonists [70,71].
Because ghrelin-producing cells are governed by enteric nervous system in
stomach mucosa, this stimulation probably is a direct effect. And this nervous
regulation likely contributes to the pre-prandial reflexive surge of ghrelin,
as shown by the report that vagotomy or blockade of vagus nerve by atropine
attenuates the increment of ghrelin induced by fasting [72]. On the other hand,
vagotomy blocks the stimulatory effect of ghrelin on food intake. Thus, the
efferent fiber of vagus nerve regulates the synthesis of ghrelin, whereas its
afferent fiber is critical for ghrelin to carry out its function. In addition,
plasma acyl ghrelin concentration is induced by a-adrenergic antagonist and b-adrenergic
agonist, indicating that sympathetic nervous system is also involved in the
regulation of ghrelin [73]. It is reported that vagotomy inhibits the secretion
of gastric ghrelin acutely, but activates its secretion in long term,
suggesting that ghrelin secretion is modulated by the balance between
cholinergic and adrenergic tones that control the enteric nervous system [73].
Physiological Status Influencing the Level of
Ghrelin
Fasting and feeding
Food intake is the most important factor that
influences ghrelin level. Circulating ghrelin concentration rises before meal
and falls after meal. Total ghrelin level increases in night and decreases
after breakfast in humans [74]. Serum ghrelin increases steadily during long
term of fasting in humans [75] and rats [28,29] and
returns to normal after re-feeding [76]. But, a new report indicates that only
acyl ghrelin but not total ghrelin changes after fasting [77], suggesting that
fasting stimulates acylation of ghrelin. In addition, the content of total
ghrelin in gastric fundus is decreased when fasting and returns to normal when
re-feeding [29], showing that fasting has more profound stimulation on the
secretion of ghrelin than on the biosynthesis. The post-prandial decrease of
ghrelin can be attributed mainly to the increase of the serum glucose
concentration. Total ghrelin, acyl ghrelin, and des-acyl ghrelin all decrease
significantly after a high-carbohydrate meal [78], in accordance with the
response of ghrelin after glucose ingestion. Other nutrients probably
contribute as well. High-fat meal induces minor [79] but more persistent [80,81] post-prandial suppression in circulating total ghrelin
than high-carbohydrate isoenergetic meal in humans. Long-term high-fat diet
reduces the plasma total ghrelin level and stomach ghrelin content in mouse
[82]. In contrast, it is also reported that serum ghrelin remains the same [83]
or increases [84] after a high-fat meal. Protein is generally believed to be
more satiety than glucose, which is consistent with a more sustainable
suppression on ghrelin by protein [85]. As reported, highprotein meal decreases
serum acyl [81] and total ghrelin [74,80,86] in humans
in both lean and obese subjects [87]. But, contradicting results have also been
reported. A protein-rich meal increases [84] or has no effect on ghrelin level
[35,42,88]. The variance in meal composition may
account for the discrepancies to large extent. The pre-prandial surge of
ghrelin may be induced largely by the expectation of food [89]. The signal is discharged
from the central nervous system and transmitted to stomach through the efferent
fiber of vagus nerve. But this cephalic control probably is not involved in the
postprandial regulation [80].
Body weight
Many reports show that ghrelin level is negatively
correlated with body mass index in humans in physiological and many
pathological statuses [42,43,67]. Plasma ghrelin
concentration is low and post-prandial decrease in ghrelin is attenuated in the
obese population [62,74]. Patients with anorexia nervosa
have significant elevated serum total and acyl ghrelin level [90], which
returns to normal when the disease is cured and the body weight restored [91].
Furthermore, total ghrelin level is inversely associated with fat cell volume
[43] and specifically in women with total fat mass and fat mass/lean mass
ratio, whereas in men it is associated with abdominal fat mass and fat
distribution index [92].
Age
In mouse, the level of acyl ghrelin steadily
increases in suckling stage (the first 3 weeks after birth). After initiation
of weaning, however, acyl ghrelin falls sharply, though the total ghrelin level
remains generally unchanged [23]. This observation suggests that certain lipid
composition in breast milk may notably stimulate ghrelin synthesis and acylation.
Similar change of ghrelin expression during development has been reported by
another study [93]. This study demonstrates that the ghrelin mRNA level
declines, but the protein concentration remains unchanged as adult mice are
aging. In humans, total ghrelin is inversely related to age in children [94].
Fasting acyl ghrelin [95] and total ghrelin [43,96]
are significantly lower in the aged population than in the youth. Besides, ghrelin mRNA level also decreases as aging in the human
adrenal cortex [97]. However, this age-dependent decline of ghrelin is
not observed in the obese population [98]. Despite the elevated basal ghrelin
level, the malnutrition-induced increase of plasma ghrelin levels may be
lacking in elderly human [99]. Additionally, the orexigenic effect of
peripheral ghrelin may also be influenced by age, as shown by experiments in
rats [100,101].
Gender
Many studies report an elevated serum ghrelin
level in female subjects relative to male ones [42,92,96].
In humans, total ghrelin level is about 3-fold higher [102] in women during the
late follicular stage of the cycle than in men. Similarly, ghrelin level is
higher in female mice than in male, especially in aged ones [93].
Pathological Status that Influences the Level
of Ghrelin
Ghrelin level alters in several disease
states. In Prader– Willi syndrome, ghrelin level is
elevated, despite the increased body weight [103]. Therefore, the excessive
ghrelin secretion may be the cause of hyperphagia and obesity in these
patients. In the case of illness-induced cachexia [104] and anorexia nervosa,
ghrelin is increased. This increase in ghrelin level may occur either as an
adaptive response to correct the abnormal energy status or as a result of
relative resistance to ghrelin. Ghrelin level is decreased in patients with
metabolic syndrome [105] and patients with polycystic ovarian syndrome [106],
in accordance with the negative correlation between ghrelin and body weight. In
the cases of diabetes mellitus type 1 and type 2, the level of ghrelin is generally
decreased and the response of ghrelin after meal consumption is attenuated or
remains similar with normal people. For details, please refer to the review by
Pusztai et al. [107]. Inflammatory diseases such as ulcerative colitis and
Crohn's disease potently increase ghrelin level [108]. This increase in ghrelin
is probably a protective response because ghrelin has a potent
anti-inflammatory effect. In addition, ghrelin is reduced in Helicobacter
pylori infection [109] and other diseases associated with gastric atrophy or
removal [110].
Summary
As summarized in Table 1, ghrelin level is
controlled by neuroendocrine system, increased at the time of negative energy
balance and decreased at the time of positive energy balance. Therefore,
ghrelin is probably an important member of the survival kit of nature [5] and
may function as a signal communicating the nutrition states of the body to the
central nervous system and help the body adjusting to its energy status, likely
through stimulation of food intake. It has been discovered that ghrelin has a
vast range of physiological functions, thus the abnormality in its secretion
possibly leads to hyper or hypophagia, obesity and other metabolic syndrome,
growth retardation, cardiovascular and/or reproduction system disorder, and
many other pathological changes. However, the current understanding about the
regulation of ghrelin level, especially its mechanism, is far from
satisfaction, with much discrepancy among studies. Unanimous conclusion on some
critical topics is still lacking, reflecting the remarkable complexity in the
regulation system, again indicating the important biological role of ghrelin.
In addition, many previous reports identify only correlation between ghrelin
and a certain agent, but cannot distinguish whether the change in ghrelin level
is the cause or effect, or they are actually independent. Thus, future works
need to discover agents that have more direct and significant effect on ghrelin
secretion, confirm the causality, and elucidate the underlying mechanism of its
regulation. It is also worth noting that some of the current reports do not
distinguish between total ghrelin and acyl ghrelin, partially because the
limitation of the detecting methods they used and partially because the ratio
between the two has been reported as constant. Since des-acyl ghrelin, the
major form of ghrelin in circulation, has now been recognized as being able to
exercise physiological roles distinct from acyl ghrelin, further study to
examine how the ghrelin and des-acyl ghrelin are differentially influenced and
to explore the change in GOAT activity will unravel the mystic of ghrelin
regulation.
Funding
This work was supported by grants from the
National Natural Science Foundation of China (30890043, 30740096, 30871194 and
30700376), and the '985' Program at
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