Ghrelin, Appetite, and Gastric Motility: The Emerging Role of The Stomach As An Endocrine Organ

Ghrelin, appetite, and gastric motility: the emerging
role of the stomach as an endocrine organ

AKIO INUI,
1
AKIHIRO ASAKAWA, CYRIL Y. BOWERS,* GIOVANNI MANTOVANI,
,
ALESSANDRO LAVIANO,
MICHAEL M. MEGUID,
AND MINEKO FUJIMIYA
Division of Diabetes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine,
Kobe University Graduate School of Medicine, Kobe, Japan; *Tulane University Health Sciences
Center, New Orleans, Lousiana, USA;

Department of Medical Oncology, University of Cagliari,
Cagliari, Italy;

Department of Clinical Medicine, University "La Sapienza," Rome, Italy;

Surgical
Metabolism and Nutrition Lab, Neuroscience Program, Department of Surgery, University Hospital,
Upstate Medical University, Syracuse, New York, USA; and

Department of Anatomy, Shiga
University of Medical Science, Otsu, Japan
ABSTRACT Recent progress in the eld of energy
homeostasis was triggered by the discovery of adipocyte
hormone leptin and revealed a complex regulatory
neuroendocrine network. A late addition is the novel
stomach hormone ghrelin, which is an endogenous
agonist at the growth hormone secretagogne receptor
and is the motilin-related family of regulatory peptides.
In addition to its ability to stimulate GH secretion and
gastric motility, ghrelin stimulates appetite and induces
a positive energy balance leading to body weight gain.
Leptin and ghrelin are complementary, yet antagonis-
tic, signals reecting acute and chronic changes in
energy balance, the effects of which are mediated by
hypothalamic neuropeptides such as neuropeptide Y
and agouti-related peptide. Endocrine and vagal affer-
ent pathways are involved in these actions of ghrelin
and leptin. Ghrelin is a novel neuroendocrine signal
possessing a wide spectrum of biological activities that
illustrates the importance of the stomach in providing
input into the brain. Defective ghrelin signaling from
the stomach could contribute to abnormalities in en-
ergy balance, growth, and associated gastrointestinal
and neuroendocrine functions.OInui, A., Asakawa, A.,
Bowers, C. Y., Mantovani, G., Laviano, A., Meguid,
M. M., Fujimiya, M. Ghrelin, appetite, and gastric
motility: the emerging role of the stomach as an endo-
crine organ. FASEB J. 18, 439456 (2004)
Key Words: GHS orexigenic signal enteric nutrition
NYP/AgRP neurons
With the discovery of the anorexigenic (appetite-
inhibiting) and adipostatic hormone leptin, studies
focused on dening neural circuits responsible for
mediating leptin actions in the brain (113). The
hypothalamus is the center for the integration of
feeding and associated autonomic, neuroendocrine,
and gastrointestinal activities. Ghrelin, identied as an
endogenous ligand for the growth hormone secreta-
gogue (GHS) receptor (14), functions as an orexigenic
(appetite-stimulating) signal from the stomach when
an increase in metabolic efciency is necessary (1517).
Ghrelin regulates, in an antagonistic manner to leptin,
synthesis and secretion of several neuropeptides in the
hypothalamus that regulate feeding and associated
hypothalamic functions. Here, we review the evidence
indicating ghrelin as a crucial missing link between the
stomach and the hypothalamus, and the clinical implica-
tion of this ghrelin/GHS receptor systemin the control of
gastrointestinal function, energy balance and growth.
GROWTH HORMONE SECRETAGOGUES (GHSs)
The pulsatile release of growth hormone (GH) from
the anterior pituitary gland is regulated by tight inter-
play between the hypothalamic growth hormone-releas-
ing hormone (GHRH) and somatostatin (18, 19).
GHRH stimulates GH synthesis and release whereas
somatostatin inhibits the release. However, several
other neurotransmitters and neuropeptides are as-
sumed to play a role in the control of GH secretion.
In the past two decades, particular attention has been
given to a new family of substances, named GH secre-
tagogues (GHSs), which show a powerful GH-releasing
effect. GHSs are non-natural, synthetic compounds
developed by Bowers and co-workers that directly stim-
ulate GH secretion (2022) (Fig. 1). The prototype
GH-releasing peptide 6 (GHRP-6) has been used as a
diagnostic tool since before the isolation of GHRH in
1982 (23). Orally active GHSs have been proposed as
an alternative to GH, insulin-like growth factor I (IGF-I)
and GHRH as a growth-promoting treatment in GH-
decient children, as well as an anabolic treatment in
elderly patients with somatopause (19, 2426).
GHSs act through specic G-protein-coupled recep-
1
Correspondence: Division of Diabetes, Digestive and Kid-
ney Diseases, Department of Clinical Molecular Medicine,
Kobe University Graduate School of Medicine, 7-5-1
Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. E-mail: inui
@med.kobe-u.ac.jp
doi: 10.1096/fj.03-0641rev
439 0892-6638/04/0018-0439 FASEB
tor(s) (27, 28) distinct from that of GHRH and exert a
powerful synergism when administered in addition to
GHRH. The GHS receptor type Ia (GHS-RIa) trans-
duces the GH-releasing effect of GHSs, whereas GHS-
RIb is a nonspliced, nonfunctional receptor mRNA
variant. GHS-RIa operates through activation of the
phospholipase-IP3 pathway and inhibition of K
chan-
nels, leading to a rise in intracellular Ca
2
. GHS-RIa is
predominantly expressed in the pituitary and hypothal-
amus and at low levels in other brain regions such as
ventral tegmental area, substantia nigra, nucleus tractus
solitarius, and hippocampus as well as peripheral tis-
sues such as heart, lung, pancreas, intestine, kidney,
and adipose tissue (2731). It has been speculated
that GHSs mimic an as yet unidentied endogenous
hormone reecting the presence of an additional neu-
roendocrine system regulating pulsatile GH secretion
(3234).
GHRELIN IS AN ENDOGENOUS GHS AND
MOTILIN-RELATED OREXIGENIC SIGNAL
FROM THE STOMACH
Recently, Kojima and Kangawa identied the 28 amino
acid peptide ghrelin as an endogenous ligand for the
orphan GHS receptor (14, 35). Ghre is the proto-Indo-
European root of the word growth. Although most
people assumed that the greatest concentrations would
be in the hypothalamus, the highest GHS receptor
activation was found in stomach extracts (14). Indeed,
Tomassetto and co-workers identied it separately from
the stomach as the motilin-related peptide (36), with
structural and effect-related similarities to the duode-
nal hormone motilin that has a key role in the regula-
tion of gastrointestinal motility (16, 17, 37) (Fig. 1).
Motilin was also known to have a GH-releasing effect
(38). Based on structural and effect-related similarities,
motilin and ghrelin are considered to represent a novel
gastrointestinal hormone family in addition to gastrin,
secretin, pancreatic polypeptide (PP), insulin, epider-
mal growth factor (EGF), and tachykinin families (17,
39, 40).
Two molecular forms of ghrelin are found in the
stomach: the 28 amino acid ghrelin having n-octanoy-
lated serine in position 3 and the 27 amino acid
des-[Gln
14
)] ghrelin produced by alternative splicing of
the ghrelin gene (14, 41). The acylation appears to be
essential for GH-releasing activity in both natural forms
of ghrelin although des-acyl ghrelin may have some
biological activities such as those acting as a survival
Figure 1. Comparison of amino acid sequences of
ghrelin and motilin (A) and chemical structures of
growth hormone secretagogues (GHSs, B) Ghrelin
is a 28 amino acid acyl-peptide esteried with
octanoic acid on Ser 3. Des-[Gln
14
] ghrelin is
produced from the alternative splicing of the
peptide coding region. Ghrelin does not have a
carboxyl-terminal amide group, but its acylation is
required for activation of growth hormone secret-
agogue (GHS) receptor-1a, a G-protein-coupled
receptor. Ghrelin and its receptor are highly con-
served across species. Human ghrelin and motilin
show 36% identity in amino acid residues. Simi-
larly, the human ghrelin receptor (GHS receptor-
1a) shows a remarkable 52% identity with the
human motilin receptor (type 1a). Ghrelin and
motilin thus represent a novel family of gastroin-
testinal hormones. MK-0677, CP-424,391, and
NNC 26-0703 are examples of nonpeptidyl GHSs,
which have been evaluated in long-term controlled
clinical studies to assess their potential benets in
a variety of disease states such as idiopathic GH
deciency and catabolic states.
440 Vol. 18 March 2004 INUI ET AL. The FASEB Journal
factor on the cardiovascular system (42). Other minor
forms of ghrelin are present in human plasma and
stomach, measured as the total immunoreactivity by the
conventional radioimmunoassay based on the carboxyl-
terminal fragment of ghrelin (43). Studies of structure
activity show that amino-terminal fragments conserving
the rst ve amino acids of the molecule display full
functional activity (44).
It is known that structural heterogeneity among
species can be of major importance for motilin (45).
Five or more positions in the 22 amino acid structure of
motilin may differ among mammalian species. The
situation is more complex in rats in which motilin is not
identied and exogenous motilin administration does
not reproduce the gastrointestinal motor effect of the
peptide. However, structural heterogeneity of ghrelin
appears minor (46), and human ghrelin is identical to
rat ghrelin except for two residues (14) (Fig. 1).
Ghrelin is expressed mainly in the stomach, by
neuroendocrine cells (X/A-like cells in rodents and
P/D1 cells in humans) in the fundus, and is secreted
into the circulation (4750). This is supported by the
nding that gastrectomy reduces plasma ghrelin con-
centrations by 65% (51). Gastric ghrelin cells show
distinctive morphology and hormone reactivity with
respect to histamine enterochromafn-like, somatosta-
tin D, glucagon A, or serotonin enterochromafn cells
(50). Both open- and closed-type cells exist in the
stomach (52), suggesting they receive both luminal and
neuroendocrine information. Lower levels of ghrelin
are found in the small and large intestine, pituitary
gland (53), (54), (55), or novel (56) cells of the
pancreatic islet, and neurons of the arcuate nucleus
(ARC) in the basal hypothalamus (14). Ghrelin has also
been detected in kidney (57), testis (58), placenta (59),
and immune cells (29). Like motilin, plasma ghrelin
concentrations rise progressively during fasting and fall
to a nadir within an hour of refeeding.
Gastric ghrelin production is regulated by nutritional
and hormonal factors (17, 49, 60, 61). Inhibitory signals
seem to include somatostatin, interleukin 1 (IL-1),
growth hormone itself, high-fat diet, and vagal tone,
whereas fasting and a low-protein diet lead to increased
expression and plasma concentrations of ghrelin. Reg-
ulation of circulating ghrelin during fasting and feed-
ing may involve distinct mechanisms and pathways. The
nding that GH lowers ghrelin expression suggests a
feedback loop between stomach ghrelin and pituitary
GH (49), although systemic ghrelin concentrations
appear not to be decreased in human acromegaly
despite high GH concentrations (62). The effects of
leptin on ghrelin production are variably reported, i.e.,
increase, no change, or decrease, which might depend
on the dosage or period of leptin administration and
feeding conditions of the animals (49, 63, 64). The
latter may be important since increased ghrelin expres-
sion is observed after high-fat feeding for a short period
that is evident only in the fasting condition (65). No
direct involvement of insulin or glucose is demon-
strated in healthy humans at physiological concentra-
tions (66). The increased secretion of stomach ghrelin
with fasting is unique when contrasted to a majority of
gut hormones whose secretion increases with food
intake and decreases with fasting.
Despite recent growth in our understanding of pe-
ripheral signals to hypothalamic pathways, ghrelin adds
a new dimension to the interplay since it is the rst gut
peptide proved to have orexigenic properties (15, 17).
Although motilin can stimulate food intake after cen-
tral administration, it produces the least effect when
administered peripherally (6769). Almost all other
gut peptides such as cholecystokinin (CCK) (7072),
glucagon-like peptide-1 (GLP-1) (73), peptide YY (PYY)
3-36 (74), and PP (64), as well as neural signals derived
from the gut consist of satiety systems. They inuence
the termination of individual meals and/or relate to
the long-term regulation of body weight. Ghrelin ad-
ministered into the periphery or cerebral ventricles
potently stimulates food intake, leading to body weight
gain in rodents (15, 16, 7577). The premeal increase
of ghrelin may trigger the desire to eat in animals and
humans.
GHRELIN ACTS ON NPY/AgRP NEURONS
IN THE HYPOTHALAMUS
Ghrelin may represent a novel orexigenic pathway that
centers on neuropeptide Y (NPY) and agouti-related
peptide (AgRP), two potent orexigenic peptides in the
hypothalamus (15, 16, 7577) (Fig. 2). Hypothalamic
NPY is synthesized primarily in ARC neurons that
project to adjacent hypothalamic areas such as the
paraventricular nucleus (PVN), lateral hypothalamic
area (LHA), and brainstem, major integration areas for
the regulation of feeding behavior, energy expendi-
ture, and gastrointestinal function (7880). NPY is a
powerful orexigenic neuropeptide. Chronic central
NPY administration results in sustained hyperphagia,
body weight gain, and a marked increase of body fat
accumulation (81). NPY promotes net energy gain by
increasing food intake, decreasing energy expenditure,
and exerting effects in peripheral tissues, including
stimulation of glucocorticoid and insulin secretion,
that favor further deposition of triglycerides in white
adipose tissue.
AgRP was identied as a 132 amino acid peptide with
25% homology to the agouti protein that is a compet-
itive antagonist of the melanocortin-1 receptor in hair
follicles (79, 80). The melanocortin system is unique in
that it consists of agonists, melanocortins such as -me-
lanocyte-stimulating hormone (-MSH), and an endog-
enous antagonist, AgRP. By antagonism of the melano-
cortin-3 receptor and melanocortin-4 receptor, AgRP
stimulates food intake and decreases energy expendi-
ture. In the brain, AgRP is synthesized exclusively in the
ARC by neurons that project to adjacent hypothalamic
areas such as the PVN and LHA. The demonstration
that AgRP mRNA is abundantly colocalized with NPY
identies NPY/AgRP neurons as a unique subset capa-
441 GHRELIN, APPETITE, AND GASTRIC MOTILITY
ble of increasing food intake via two mechanisms: by
increasing orexigenic NPY signaling on the one hand
and decreasing anorexigenic melanocortin signaling
on the other (79, 82).
Arcuate NPY/AgRP neurons appear to play an im-
portant role in energy homeostasis, transducing
changes of body fat content into adaptive feeding
responses that are communicated by leptin and insulin,
two adipostatic hormones with their circulating levels
generally proportional to energy stores in adipose
tissue (79). The ARC is strategically positioned to be in
direct communication with peripheral signals because
of the absence of bloodbrain barrier (BBB). Thus, the
NPY/AgRP system senses and respond to a wide variety
of hormones and nutrients relevant to both short- and
long-term aspects of the regulation of energy balance.
Defective inhibition of NPY/AgPP neurons can have
major consequences: hyperphagia, reducing energy
expenditure, disturbances of glucose and lipid metab-
olism, and obesity (7, 9, 11, 7883).
NPY/AgRP gene expression is up-regulated during
periods of negative energy balance such as fasting and
insulin-decient diabetes, although the magnitude of
the respective response may differ (79). Leptin and
insulin subserve overlapping functions as principal
inhibitors of NPY/AgRP neurons; a decrease in inhib-
itory input from these adiposity signals activates NPY/
AgRP and induces hyperphagic responses. These re-
sponses are mediated in part by the two orexigenic
peptide systems in the LHA: melanin-concentrating
hormone (MCH) and orexin, and projections from the
ARC NPY/AgRP synapse on the MCH-or orexin-pro-
ducing neurons (6, 11, 84, 85).
GHRELIN IS A MISSING LINK BETWEEN
ENTERIC NUTRITION AND CENTRAL
REGULATION OF ENERGY BALANCE
AND GROWTH
The stimulatory action of ghrelin on food intake is
mediated by the NPY/AgRP pathway, since blockade of
NPY Y1 feeding receptors or immunoneutralization of
AgRP attenuates ghrelin-induced feeding (16, 76, 77).
Consistent with this, the majority of NPY neurons in the
arcuate nucleus express GHS receptor (86), and 50%
of cells activated (that express c-Fos mRNA) after GHS
administration contain NPY mRNA (87). Peripherally
administered ghrelin induces Fos specically in the
ARC, and 90% of the Fos-positive neurons express
NPY and coexisting AgRP (88, 89). NPY and AgRP
mRNA expression in the ARC are increased after
ghrelin administration to fed rats (16, 76, 77, 90). The
orexigenic activity of ghrelin is consistent with ndings
reported earlier showing that central administration of
GHSs such as GHRP-6 and KP102 stimulates food
intake and weight gain in rats (9194). Chronic
GHRP-2 treatment stimulates the accumulation of adi-
pose tissue mass in NPY-decient mice as in controls,
paralleled by an increase of hypothalamic AgRP mRNA
expression (95). Central GHSs also activate Orexin
(but not MCH) neurons, and ghrelin-induced feeding
is attenuated by pretreatment with anti-orexin (but not
anti-MCH) IgGs or in orexin knockout mice, indicating
that ghrelin may selectively activate certain orexigenic
pathway from NPY/AgRP to orexin (6, 11, 96, 97).
The ability to delete a gene of interest in a tissue-
specic manner is a considerable advantage in studying
Figure 2. The regulation of secretion and actions of ghrelin
on the gut-brain axis Ghrelin has been recognized as an
important regulator of GH secretion and energy balance.
Orexigenic and adipogenic ghrelin is produced by and
released from the stomach in response to fasting and hypo-
glycemia. Ghrelin and leptin regulate gastric motility, appe-
tite, and body weight by counter-regulating the same hypo-
thalamic signals such as neuropeptide Y (NPY) and agouti-
related peptide (AGRP), the two extraordinarily potent
orexigenic peptides that simultaneously decrease energy ex-
penditure. NPY and AGRP are coproduced in the arcuate
nucleus (ARC) and act in the paraventricular nucleus (PVN)
and adjacent hypothalamic areas such as the lateral hypotha-
lamic area (LHA) in which orexin neurons exist. The NPY/
AgRP neurons transduce changes of body fat contents (as
communicated by leptin and insulin) into adaptive feeding
responses. Ghrelin is a novel neuroendocrine peptide that
links the gastrointestinal system and the hypothalamic orexi-
genic pathway. Other gastrointestinal peptides such as gluca-
gon-like peptide-1 (GLP-1), cholecystokinin (CCK) -8, pep-
tide YY (PYY)3-36 and pancreatic polypeptide (PP) produces
satiety through endocrine and/or neural pathways. Plus signs
denote stimulatory input, and minus signs inhibitory input.
Positive and negative regulators of body adiposity are shown
as red and blue, respectively. VMH, ventromedial hypothala-
mus; DVC, dorsal vagal complex.
the function of the gene (8, 9). Transgenic rats were
recently created using an antisense GHS receptor
mRNA under the control of the promoter for tyrosine
hydroxylase to selectively attenuate GHS receptor pro-
tein expression in the ARC (98). Transgenic rats have
an expected phenotype with decreased food intake,
lower body weight, and less adipose tissue; female rats
show decreased GH secretion and plasma insulin-like
growth factor-1 concentrations. This indicates the im-
portance of ARC in ghrelins action, also supported by
experiments in rats treated neonatally with monoso-
dium glutamate (MSG) (99). MSG causes specic le-
sions in the ARC, resulting in a 7090% destruction of
neuronal cell bodies including GHRH-, NPY-, and
AgRP-containing neurons (99101). In these rats, gh-
relin shows a markedly diminished GH release and a
failure to stimulate food intake. These results indicate
that the primary site of action of ghrelin on appetite
and GH release resides in the ARC, where circulating
ghrelin is able to gain access (96, 102). Although
peripheral hormones such as leptin and insulin have
been shown to cross the BBB by saturable and nonsat-
urable mechanisms (103, 104), the transport process
for ghrelin appears to be complex with only limited
ability to penetrate into the brain areas within the BBB
(105).
The isolation of ghrelin from the stomach was thus a
landmark nding not only in the GH eld, but also in
appetite and energy metabolism regulation (1517, 60,
7577). During starvation, when leptin levels rapidly
decline, circulating ghrelin levels increase, leading to
the stimulation of NPY/AGRP production in the ARC
(17). Therefore, ghrelin and leptin are complemen-
tary, yet antagonistic, signals of the regulatory feedback
loop that has developed to inform the brain about the
current status of acute and chronic energy balance
(Fig. 2). Ghrelin is able to act on leptin-responsive
arcuate neurons, the opposite effect of which may serve
as a neurophysiological correlate of the orexigenic and
anorexigenic effects of ghrelin and leptin (106108).
This view is supported by a recent nding that central
leptin gene therapy blocks high-fat, diet-induced
weight gain, hyperleptinemia, and hyperinsulinemia
yet increases circulating ghrelin levels (109). It is likely
that the ghrelin and NPY/AgRP systems respond to
fasting and negative energy balance at gastric and
hypothalamic levels; ghrelin secretion may be more
complex, responding to dietary manipulations, since
stomach ghrelin cells are exposed to the luminal con-
tents. The effects of GH in promoting the growth of soft
tissue such as cartilage, together with the potent GH-
releasing and orexigenic effect of ghrelin, indicate an
involvement of the stomach in the regulation of growth
processes (17, 76).
Ghrelins effect on body weight in rodents is due in
part to altered metabolism and energy expenditure.
Ghrelin reduces fat utilization and core body tempera-
ture in rats (15, 96) and reduces oxygen consumption
in mice (16). The brain controls energy expenditure
via the sympathetic nervous system, which heavily in-
nervates thermogenic tissues such as brown adipose
tissue and skeletal muscle (110). Ghrelin can reduce
energy expenditure via NPY/AgRP pathway although
the precise mechanism of the anabolic actions has yet
to be fully characterized (16). The brain also affects
energy expenditure by means of the hypothalamic-
pituitary-thyroid axis. Ghrelin and other GHSs have
been shown to decrease TSH levels and to stimulate the
hypothalamic-pituitary-adrenal (HPA) axis, both result-
ing in an induction of a positive energy balance (111,
112). Ghrelin may trigger increased release of GH and
ACTH during fasting and be a key player connecting
the nutritional state with endocrine changes. Leptin
signals these endocrine axes in an opposite manner
when a positive energy balance exists.
Ghrelin and leptin show antagonistic activity on
gastrointestinal functions (16, 17). Ghrelin increases
gastric acid secretion, motility, and emptying (16, 113)
whereas leptin decreases them. The gastro-prokinetic
activity of ghrelin is independent of its GH-releasing
effect and is likely to be mediated by the vagal-cholin-
ergic muscarinic pathway (16, 37, 113). Ghrelin is a
potent gastro-prokinetic agent that accelerates the nor-
mal emptying process in rats and mice with doses
compatible to those required to stimulate appetite and
GH release (16, 114). Ghrelin also accelerates the
transit of the small intestine but not that of the colon.
The 28 amino acid and the des [Gln
14
]-27 amino acid
octanoylated forms appear to be equally bioactive
(114). It was reported that calcitonin gene-related
peptide (CGRP) 8-37, an antagonist of CGRP, is among
the few agents with benecial effects on the inhibition
of gastric emptying after surgery (115). Ghrelin is more
active than CGRP 8-37 and is capable of reversing the
postoperative gastric ileus in which motilin or motilin
receptor agonist erythromycin is without effect (114).
Therefore, ghrelin may be the most potent drug tested
to accelerate gastric emptying in rodents.
Plasma motilin concentrations are known to be
highly variable during the interdigestive fasting period
(34, 39, 116). Periodic and recurrent increases in
motilin are seen, which are synchronized with the
migrating motor complex (MMC) of the fasting gastro-
intestinal tract. MMC is a recurrent pattern of cyclic
occurring motor activity and can be divided into three
distinct phases: phase I characterized by motor quies-
cence; phase II consisting of irregular motor activity;
and phase III, a short burst of rhythmic contractions
(37, 117119). In dogs and humans, the rises in circu-
lating motilin regulate the appearance of the phase III
contractions from the antroduodenal region to the
distal gut (37, 42). We recently examined the effect of
ghrelin on the gastroduodenal motility in a freely
moving conscious rat model that permits the measure-
ment in the physiological fed and fasted states of the
animals (Fig. 3) (120, 121). When ghrelin is adminis-
tered into the lateral cerebral ventricle or the tail vein
of fasted animals, it potentiates phase III-like contrac-
tions in the antrum and duodenum. When ghrelin is
administered in fed animals, it disrupts the fed motor
activity and induces phase III-like contractions despite
the presence of food in the stomach. The delayed
occurrence of fasted motor activity after intravenous
ghrelin is due to the low intragastric pH, which is
normally involved in the postprandial interruption of
fasted motor activity (118, 122). Vagal and nonvagal
pathways may mediate these actions of ghrelin since
vagotomy blocks the responses by central, but not
peripheral, administration of ghrelin (114). Vagotomy
is reported not to block the inhibition of pancreatic
protein secretion by ghrelin, which may be exerted at
the level of intrapancreatic neurons (123).
Previous studies demonstrated that food intake and
gastrointestinal fed and fasted motor activities are
closely related (124, 125). NPY not only induces food
intake in fed animals but also changes gastroduodenal
motor activity from fed to fasted pattern (Fig. 3) (120).
This motor effect of NPY is mediated by the Y2 receptor
rather than the Y1 and Y5 receptors, which mediate
appetite stimulation by the peptide (78). Administra-
tion of anti-NPY antiserum into the cerebral ventricle
abolishes the fasted motor activity and induces fed-like
contractions, indicating an involvement of the endog-
enous NPY and Y2 receptor system in the generation of
fasted motor activity (120). AgRP is also able to induce
fasted motor activity in fed animals (unpublished data).
Therefore, the interdigestive phasic contraction can be
correlated well with the onset of hunger sensation and
initiation of feeding. On the other hand, urocortin, a
potent anorexigenic peptide belonging to corticotropin-
releasing factor (CRF) family, induces fed-like motor
activity when administered centrally or peripherally in
fasted animals (126). CCK is another example that sup-
presses feeding and MMC following either route of ad-
ministration (127129). The nding that the gastroduo-
denal motor effect of ghrelin is blocked not only by the
GHS receptor antagonist [D-Lys3] GHRP-6, but also by
immunoneutralization of NPY in the brain, indicates that
NPY neurons mediates this effect under the presence of
the vagus nerve (Fig. 3) (121). Since ghrelin antagonist/
antiserum treatment reduces body adiposity and gastric
emptying, ghrelin may be critically involved in these
Figure 3. Effects of ghrelin and NPY
on the motor activity of conscious rat
antrum and duodenum measured by
the manometric method The fasted
motor activity known as the migrating
myoelectric complex (MMC,) is re-
placed by the fed motor activity con-
sisting of irregular contractions after
food ingestion (A). Administration of
ghrelin into the tail vein (B) or the
cerebral ventricle of fed rats power-
fully affects the motility, changing the
fed pattern into the fasted pattern
despite the presence of food in the
stomach. This effect is mediated by
the ghrelin receptor since the GHS
antagonist [D-Ly3] GHRP-6 adminis-
tered by the same route blocks it (C).
Administration of NPY into the cere-
bral ventricle also produces the MMC
in fed rats (D). Immunoneutralization
by anti-NPY antiserum administered
intracerebroventricularly blocks not
only the MMC induced by exogenous
NPY, but also the MMC induced by
exogenous ghrelin (E) or that occur-
ring physiologically during fasting (F )
in the animals.
alterations (17, 65). Ghrelin thus illustrates the impor-
tance of functional interdependency of the stomach and
hypothalamus for the integration of feeding and associ-
ated autonomic, neuroendocrine, and gastrointestinal
functions (Fig. 2).
It is reported that NPY and Y2 agonist inhibit gastric
emptying of solid or liquid meals (130) and a Y2 agonist
applied to the dorsal vagal complex suppresses thyro-
tropin-releasing hormone (TRH) -stimulated gastric
motility (131). Since the ghrelinNPY pathway is down-
regulated after feeding, it is not known whether it plays
an important role in postprandial gastrointestinal phys-
iology. It is generally agreed that motilin's physiological
effect is limited to the interdigestive state (132). Al-
though PYY3-36 is a physiological satiety factor acting
on the NPY Y2 receptor in the ARC, it does not affect
gastric emptying (74).
Although peripherally administered ghrelin has no
effect on gastric acid secretion in pylorus-ligated con-
scious rats, central ghrelin produces a long-lasting
gastric inhibitory action (133) (though stimulatory
under anesthesia; 134, 135). Distinct pathways may be
involved in gastric and feeding activities, since
EP40737, a hexapeptide that stimulates GH release but
is devoid of effects on feeding (136), is able to reduce
gastric acid secretion (133). It remains to be deter-
mined whether a small amount of ghrelin produced in
the hypothalamus (which hardly contributes to circu-
lating ghrelin) (62) is physiologically relevant and
involved in the regulatory feedback loop (Fig. 2).
Ghrelin-like immunoreactive neurons are observed in
the ventral part of the ARC (137) or the internuclear
space between the PVN, ARC, VMH, and DMH (108).
The axons of hypothalamic ghrelin neurons abut NPY
axons presynaptically in the ARC and PVN and may
increase secretion of GABA, NPY, and AgRP (108).
THE STOMACH IS AN IMPORTANT
COMPONENT OF ENERGY HOMEOSTASIS
EQUATION
Gastric emptying plays an important role in regulating
food intake (120, 124, 126, 138146). Gastric disten-
sion acts as a satiety signal to inhibit food intake, and
rapid gastric emptying is closely related to overeating
and obesity (139, 140). Lesions of the ventromedial
nucleus (VMH) of the hypothalamus are known to
disrupt autonomic output controlling the stomach and
increase the normally slow daylight rate of gastric
emptying of regular diet (140). The abbreviated satiat-
ing effect of food resulting in such gastric acceleration
is thought to be a major cause in the obese VMH
syndrome, along with other autonomic defects such as
insulin hypersecretion and reductions in fat mobiliza-
tion and thermogenic capacity (5, 7, 9).
Most anorexigenic molecules such as CCK, CRF, and
IL-1 not only suppress feeding but also decrease gastric
transit1 (24, 126, 139, 141147). The inhibitory effect
of peripherally administered CCK-8 on the rate of
gastric emptying has been shown to contribute to its
ability to inhibit food intake in various species (16, 138,
148151). The inhibitory effects on gastric emptying by
CRF, CRF type2 receptor agonist urocortin, and their
analogs paralleled the inhibitory effects on food intake
(139). The ob/ob mice are another example that shows
rapid gastric emptying and overeating at the develop-
ment of obesity (1, 6, 16, 139). Urocortin potently
decreased food intake and reversed rapid gastric emp-
tying in the animals (139). Repeated administration of
urocortin decreased body weight and improved glyce-
mic control, indicating that the decreased absorption
rate of nutrients is benecial not only to decrease food
intake but also to decrease the requirements of insulin
in obese diabetic animals. GLP-1 or its potent analogs
may be effective in treating such diabetic animal mod-
els and humans (73, 152) although they may affect
sympathetic outow (153).
Recently leptin and its receptor were identied in
gastric mucosa in animals (154, 155) and humans (156,
157) (Fig. 2). Gastric leptin can be released into the
blood and gastric juice after feeding, insulin-induced
hypoglycemia, or infusion of CCK-8, pentagastrin, and
secretin, providing evidence that leptin is a stomach-
derived protein (154, 156, 157). Gastric leptin may have
a role in appetite regulation by acting directly in the
hypothalamus or in synergy with CCK via the vagal
pathway (72, 157159) or by modifying absorption of
dietary protein and fats (160). How leptin interacts with
ghrelin in the stomach needs to be determined. How-
ever, the existence of a regulatory feedback loop involv-
ing the stomach suggests a fascinating role of ghrelin
and leptin as an interface between regulatory centers in
the brain of nutritional intake, gastrointestinal func-
tion, metabolic control, and growth regulation.
Enterostatin may be another component of this
system, formed through the processing of pancreatic
procolipase, a protein necessary for intestinal fat diges-
tion (161). It is also produced in chief cells of the
stomach as part of procolipase as well as in enterochro-
mafne cells independent of procolipase, most fre-
quently in the antral part of the stomach extending all
along the intestine down to the ileum (162). Enterosta-
tin increases during fat feeding, where it is found in
circulating blood as well as in intestinal lumen and the
lymph. When reducing food intake by either peripheral
or central administration, enterostatin behaves as a
physiological satiety substance, inducing early satiety
(163). During long-term treatment, enterostatin is able
to reduce body weight in rodents when fed a high-fat
diet. A reduced body weight may be explained by a
decreased food intake involving delayed gastric empty-
ing (164) and an increased energy expenditure
through activation of the sympathetic nervous system
and increased expression of uncoupling protein 1 in
brown adipose tissue. The mechanism of action for
restriction of fat intake may involve serotonin, opioids
and dopamine, which are components of the reward
system (161). A more complete understanding of how
the stomach regulates energy balance and other brain
functions thus depends upon the elucidation of the
gastric machinery and network of which molecules like
ghrelin, leptin, and enterostatin are a part.
VAGAL AFFERENT NEURONS ARE AN
IMPORTANT TARGET FOR PEPTIDE ACTIONS
At least part of ghrelin and leptin signaling from the
stomach is mediated by an ascending neural network
through the vagus nerve and brainstem nuclei that
ultimately reaches the hypothalamus (16, 158, 165).
Abdominal vagal afferents have their cell bodies in the
nodose ganglion. Neurotransmitters and receptors syn-
thesized within the ganglion and subsequently trans-
ported to the nerve terminals are being identied
(166). The presence of leptin within the gut, the
discovery of the leptin receptor on the vagus nerve, the
modulatory effects of leptin on intestinal vagal mech-
anoreceptors, and the known involvement of the vagus
and other afferents in transmitting satiety all suggest a
need to evaluate the potential of other feeding regula-
tory hormones located within the hypothalamus
and/or gut on vagal nerve function (166170).
Orexins may be another example, produced in neu-
rons and endocrine cells in the gut (171) in addition to
neurons in the LHA. A recent study localized the
orexin-1 receptors to vagal afferent neurons that also
expressed CCK-1 (A) and leptin receptors and showed
that orexin-A inhibited the response of afferent nerve
bers to CCK (172). The mechanism by which CCK
signals to the brain on satiety is known to include activa-
tion of CCK-1(A) receptors produced in vagal afferent cell
soma and transported peripherally (173175). The dual
CCK-leptin signals are transmitted to the nucleus tractus
solitarius, then hypothalamic sites, of which the PVN
appears to be the primary target, orchestrating appropri-
ate food intake alterations (159).
Ghrelin receptors are also synthesized in vagal affer-
ent cell soma and intravenous ghrelin suppresses ring
of the vagal afferents (16, 165). Selective chemical
blockade by capsaicin or surgical deafferentation of the
gastric vagal nerve blocks the Fos expression in the ARC
and the feeding response to peripherally administered
ghrelin. The nding that vagotomy eliminates the GH
response to ghrelin indicates a novel vagus-mediated
GH secretion pathway (165) in addition to the known
vagus-mediated regulation of gastrointestinal motility
and secretion, behavioral responses such as satiety, and
pathophysiological sensations and reexes such as nau-
sea and vomiting (166). These data stress the impor-
tance of the vagus nerve in conveying ghrelin signals to
the brain although the extent of the dependence needs
to be further examined.
CLINICAL IMPLICATIONS
GH deciency
Data have shown that the combined administration of
GHRH and GHSs appears to be the most potent
stimulus of GH release in humans (24, 176, 177). It may
be a convenient, safe, and reliable test for the diagnosis
of GH deciency. Administration of GHS is preferable
to direct administration of GH because it induces a
more physiological prole of GH secretion, not bypass-
ing the feedback loop controlling the GH-IGF-1 axis
(178). Potential targets for GHS compounds include
children (179) and adults with GH deciency associ-
ated with alterations in body composition, increased
prevalence of cardiovascular morbidity, and shortened
life expectancy (180, 181). The majority of GH-de-
cient subjects respond to GHS, which can be adminis-
tered intravenously, intramuscularly, subcutaneously,
orally, intranasally, or transdermally (17, 19, 182). GHS
analogs could be used in all pathophysiological states
where the administration of moderate GH doses has
been shown to be effective such as aging, catabolic
states, and osteoporosis. Although ghrelin levels in
GH-decient subjects are not signicantly different
from controls (183), it remains to be seen whether
some subjects can lack ghrelin and have growth-re-
tarded phenotype and whether the ectopic production
of ghrelin can lead to acromegaly (23). Ghrelin has
been shown to regulate expression of a pituitary-spe-
cic transcription factor, Pit-1, suggesting a role in
somatotroph differentiation in addition to GH secre-
tion (184). Transgenic animals that overexpress or
delete the ghrelin gene may help address these issues.
Obesity
Obesity is characterized by a blunted GH secretion that
might help to maintain this state and is reversed by
weight loss (24, 185). Fasting plasma ghrelin concen-
trations in obesity are signicantly lower and are nega-
tively correlated with body mass index, percent body
fat, and/or fasting insulin and leptin concentrations
(180, 187). The low levels of ghrelin might contribute
to the decreased GH secretion in obese patients.
Plasma ghrelin levels are also negatively correlated with
plasminogen activator 1 (PAI-1) levels that are elevated
in insulin-resistant subjects and associated with in-
creased cardiovascular risk of atherothrombosis (188).
The decreased ghrelin secretion in established obesity
may be a physiological adaptation to long-term positive
energy balance although a particular subset of obesity
may be associated with high levels of ghrelin (189).
Despite its low levels, ghrelin may act to maintain the
increased body weight as with NPY (190, 191), since
weight loss increases ghrelin levels that are correlated with
the extent of weight loss (189). The lack of suppression of
plasma ghrelin after a meal in obese subjects may contrib-
ute to increased food consumption (192).
A recent study suggests that ghrelin is a long-term
regulator of body weight rather than a short-term,
meal-related orexigenic signal in humans (193). Gastric
bypass surgery is an important treatment for morbid
obesity that can produce prolonged weight reduction
(194). Gastric bypass subjects exhibit markedly differ-
ent ghrelin secretary proles, with markedly reduced
cumulative secretion as well as loss of premeal increase
or diurnal variability that normally peaks between 12
and 2 am and nadirs at 910 am. Conversely, bypass
subjects exhibit normal postprandial insulin secretion
and diurnal leptin cycling. Therefore, suppression of
plasma ghrelin by gastric bypass surgery can contribute
to the efcacy of this procedure as weight reduction
therapy in addition to the physical restriction of the
stomach (gastric pouch) and the reduction of nutrient
digestion and absorption (long Roux-en-Y) (195).
Prader-Willi syndrome is the most common form of
human syndromic obesity, occurring in 1 of 10,000
16,000 live births (196198). It is characterized by
severe hyperphagia, GH deciency, hypogonadism,
neonatal hypotonia, dysmorphic features and cognitive
impairment. Although Prader-Willi syndrome arises
from functional loss of several paternally expressed
genes in an imprinted domain on chromosome 15,
mediators of the phenotype are not well known (9,
196). Recent studies demonstrated that while obesity
per se is associated with low ghrelin levels, that accom-
panied by Prader-Willi syndrome is associated with
elevated ghrelin with no decrease after a meal (197,
198). The increased ghrelin levels are comparable to or
higher than those reported to stimulate appetite and
food intake during exogenous ghrelin administration
in humans (199), suggesting a role of ghrelin in the
pathogenesis of hyperphagia in Prader-Willi syndrome.
It remains to be determined whether elevated ghrelin
participates in the GH deciency by such mechanisms
as paradoxical override inhibition described in contin-
uous GHRH stimulation of GH (197, 200). Interven-
tions that lower plasma ghrelin levels or antagonize its
orexigenic effects warrant consideration in treatment
of this type of obesity. Gastric bypass may have less
efcacy in Prader-Willi patients than in other obese
children and adolescents (201, 202). Ghrelin levels are
low or normal in patients with other genetic obesity
such as those with leptin receptor mutation or melano-
cortin 4 receptor mutation (197).
Rapid gastric emptying may have a role in apparent
leptin resistance since the gastromotor abnormality is
quantitatively the most important precondition of ex-
cess fat deposition and the hyperphagic pattern of
frequent meals in some animal models of obesity (140).
Rapid gastric emptying has been reported in clinically
obese populations, and the appetite suppressant, anti-
obesity agent fenuramine (although withdrawn from
the global market due to the unfortunate development
of valvuloplasty) (10, 203) may reduce food intake by
slowing gastric emptying and so extending the satiating
effect of a meal (140, 204, 205). Gastric emptying
half-time as assessed by
13
C-octanoic acid breath test is
correlated with fasting plasma ghrelin levels in healthy
humans, though this could be interpreted as a physio-
logical reaction to balance of gastric motor function
(206). A failure to demonstrate the prokinetic effect of
a physiological dose of exogenous ghrelin is reported
when gastric emptying is measured using the paraceta-
mol absorption test (199). More studies, especially
those using radionuclide techniques (207), are needed
to evaluate the actions of ghrelin/GHS on gastric
emptying in humans. It remains to be examined
whether ghrelin/GHS antagonist is effective in slowing
abnormal gastric emptying and ameliorating excessive
food intake and fat deposition in humans as it does in
animals (61).
Gastrointestinal disorders
The benecial effect of ghrelin in an animal ileus
model (107) is interesting. Abdominal surgery inhibits
gastric emptying and digestive motor activity in exper-
imental animals and humans (114, 208, 209). Abdom-
inal surgery with manipulation of viscera induces post-
operatively a state of digestive motor inactivity that may
occasionally be overly prolonged while associated with
signicant morbidity; these patients could certainly
benet from a specic and effective treatment. At-
tempts by various prokinetics such as acetylcholine,
cisapride, and motilide to stimulate directly or via the
afferent neural pathways frequently gave disappointing
results (208210). However, ghrelin is the most potent
drug to reverse postoperative gastric ileus in the animal
model (114). It should be examined whether ghrelin or
GHS compounds could help prevent postoperative
gastric ileus in humans.
Gastroparesis is associated with many diseases, the
most frequent cause of which is diabetes mellitus.
About one-half of patients with insulin-dependent or
non-insulin-dependent diabetes have delayed gastric
emptying. Diabetic gastroparesis is generally ascribed as
a consequence of autonomic neuropathy although
hyperglycemia per se may contribute to the pathogen-
esis of disordered gastric motility (211). Motilin and
erythromycin are able to accelerate gastric emptying in
such patients probably by direct effects on smooth
muscles (132, 207, 212, 213). Due to the potent proki-
netic activity in animals, ghrelin and GHS compounds
may also offer therapeutic potentials to treat the disor-
der.
Short bowel syndrome is a condition that occurs after
resection of a substantial portion of small intestine and
is characterized by malnutrition. The malnourished
patients have lower plasma ghrelin concentrations in
contrast to the expected increase (214). This indicates
that signicant amounts of ghrelin are produced by
neuroendocrine cells in the intestine and the decrease
in plasma ghrelin levels may contribute to decreased
appetite in these patients. It is possible that the short
bowel feeds back on the release of ghrelin.
Helicobacter pylori is known to modify leptin expres-
sion in the gastric mucosa (215). After eradication of H.
pylori, median and integrated plasma ghrelin is in-
creased signicantly, making it likely that the associa-
tion of H. pylori and appetite is mediated in part
through ghrelin. Although there are no studies in
adults illustrating whether H. pylori-positive subjects
have a lower body weight than negative controls, H.
pylori children may have a high incidence of growth
retardation (216221), as demonstrated in experimen-
tal animals (222).
A recent study indicates a potent protective effect
against ethanol-induced gastric lesions by central ghre-
lin and a partial peripheral protective effect (223). This
effect of ghrelin is mediated by endogenous nitric
oxide (NO) release and requires the integrity of sen-
sory nerve bers. Since acute hemorrhagic and erosive
gastropathy may represent a potentially life-threatening
condition, ghrelin may deserve attention as a new
pharmacological tool for the treatment.
Cachexia
Recent studies suggest that ghrelin may be a clinical
marker of catabolism (17). Elevated levels of circulating
ghrelin are observed in cachexia associated with
chronic heart failure (224) or liver cirrhosis. Indeed,
GHSs such as MK-0677 and GHRP-2 are reported to
reverse diet-induced catabolism and to improve alter-
ations in the somatotrophic axis and protein catabolism
in patients with prolonged, severe illnesses (24, 225,
226).
GH has been used as a potential anabolic agent to
counteract muscle wasting associated with surgical
stress, sepsis, glucocorticoid administration, AIDS, and
cancer (227, 228). GH stimulates whole body and
muscle protein synthesis under some conditions. Ghre-
lin or ghrelin/GHS compounds may improve the treat-
ment of such patients, especially aging patients in
whom reduced GH secretion, reduced muscle mass,
and anorexia are often observed (227). The age-related
decline of plasma ghrelin may explain in par, the
somatotrophic dysregulation and anorexia of elderly
subjects (229). Chronic treatment of elderly with MK-
0677 is reported to reverse age-related changes of the
GH/IGF-1 axis and to improve the quality of sleep in
healthy elderly subjects (25, 230).
The impressive orexigenic effect of ghrelin adminis-
tered peripherally in rodents indicates it warrants eval-
uation in treating conditions associated with excessive
weight loss such as cancer. Weight loss is a potent
stimulus to food intake in normal humans and animals.
Therefore, the persistence of anorexia in cancer im-
plies a failure of this adaptive feeding response (147,
231). Cytokines, proposed mediators of the cachectic
process, may play a pivotal role in long-term inhibition
of feeding by mimicking the hypothalamic effect of
excess negative feedback signaling from leptin (147,
231). IL-, a cytokine known to be elevated in malig-
nancy (147, 232), decreases not only hypothalamic NPY
mRNA expression but also gastric ghrelin mRNA ex-
pression, and peripherally administered ghrelin re-
verses the IL-1-induced loss of appetite and body
weight (16, 233).
It is known that NPY feeding systems are dysfunc-
tional in such wasting models as tumor-bearing animals
(147, 231, 234240). NPY biosynthesis in the ARC may
be elevated in animal models of cachexia, consistent
with an adaptive response (240, 241). However, NPY
release in the hypothalamus or the orexigenic potency
of NPY is markedly attenuated compared with the
controls (240, 241). As with NPY, plasma concentra-
tions of ghrelin may be increased in some animal
models of cachexia, and ghrelin may display markedly
blunted orexigenic potency (241) although its thera-
peutic efcacy may depend on the animal model used.
Ghrelin is reported to be elevated in cachectic patients
with lung cancer and anorectic patients after chemo-
therapy (242). Since orally bioavailable GHSs with
longer lasting potency have been developed and ad-
ministered safely to humans, it remains to be deter-
mined whether these compounds may have an effect in
the treatment of cancer anorexia-cachexia syndrome,
except for ghrelin-responsive malignancy. Treatment
options for cancer anorexia are few; the progesterone-
like hormone megestrol acetate is the most extensively
characterized agent in animals and humans, which acts
through NPY to increase food intake and body weight
(232, 243).
The gastro-prokinetic activity may be benecial since
most of the wasting conditions are associated with
delayed gastric emptying (124, 147). Erythromycin has
been shown to accelerate delayed gastric emptying
associated with cancer therapy and other critical con-
ditions (37, 246).
Eating disorders
Anorexia nervosa is a psychopathologic disorder that
presents with neuroendocrine alterations reecting
starvation (245). Patients experience hunger, but are
prevented from eating by intense fear of losing control
over eating and becoming overweight. Plasma ghrelin
concentrations in patients with anorexia nervosa are
signicantly elevated compared with those of healthy
controls, although there may be some patients with
normal (not increased) ghrelin levels (186, 221, 229,
246). Plasma ghrelin levels do not fall after food intake,
suggesting that a single meal is not sufcient to sup-
press the drive to eat in the subjects (247). NPY
concentrations in the cerebrospinal uid are also in-
creased in anorexia nervosa (245, 248). Ghrelin levels
return to normal after partial weight recovery, suggest-
ing it reects a physiological effect to compensate lack
of nutritional intake and energy stores (249). Whether
this reects a state of ghrelin resistance analogous to
the model of leptin resistance is not known (249). The
increased ghrelin might explain relatively high plasma
concentrations of growth hormone in anorexic pa-
tients. Although there may be no difference in ghrelin
secretion between restrictive vs. bulimic anorexia ner-
vosa (246), plasma ghrelin is signicantly elevated in
patients with bulimia nervosa (250), suggesting that
abnormal eating behaviors with habitual binge eating
and purging may inuence ghrelin secretion. It re-
mains to be examined whether binges in bulimia
nervosa are the consequence of elevated ghrelin.
Others
Hyperphagia and altered fuel metabolism are promi-
nent features of uncontrolled diabetes mellitus in both
animals and humans (251). In an insulin-decient
diabetes model induced by the cell toxin streptozo-
tocin, plasma ghrelin concentrations are signicantly
elevated with a concomitant decrease in plasma leptin
and an increase in hypothalamic NPY gene expression
(252). All of these changes are reversed by insulin
treatment. The increased food intake seen in the
animal model is partially reversed by administration of
a ghrelin receptor antagonist [D-Lys-3]-GHRP-6, sug-
gesting that increased ghrelin together with decreased
leptin causes hyperphagia via the NPY (252, 253) and
AgRP (251) pathway. Although there may be no signif-
icant difference in basal plasma ghrelin concentrations
between healthy subjects and type 2 diabetics (186), the
pathophysiological signicance of ghrelin in diabetic
hyperphagia that makes it difcult for patients to
adhere to diet therapies should be examined in uncon-
trolled diabetics.
Ghrelin and GHS-RIa are present in endocrine pan-
creas (254). Ghrelin produces signicant hyperglyce-
mia, which is followed by a reduction in insulin secre-
tion in humans (254). Coupled with the observation
that chronic treatment with MK-0677 induces hypergly-
cemia (albeit with hyperinsulinemia) in elderly subjects
(255), this evidence indicates that ghrelin may play a
role in glucose metabolism.
Ghrelin cells are detected in human fetal stomach
(50) as well as intestine, pancreas (56), and lung (256)
long before ECL and chief cells of the stomach, the
latter of which are a major source of leptin (154). The
early and widespread development of ghrelin cells in
embryonic tissues may indicate an important role for
fetal ghrelin either in promoting body growth through
stimulation of GH release or by fullling some local
trophic and morphogenetic role (50, 56, 256, 257).
Ghrelin is present in the placenta, where all the main
regulatory components (GH, GHRH, IGF-1, and soma-
tostatin) appear to be involved in fetal growth in
animals and humans. Higher levels of circulating ghre-
lin and lower reductions after intravenous glucose are
seen in infants born small for gestational age who show
greater infancy weight gain and catch-up growth (258).
Ghrelin may have benecial hemodynamic effects in
humans via reducing cardiac afterload and increasing
cardiac output without increasing heart rate (259).
Ghrelin may cause inhibition of growth in breast cancer
(260), thyroid cancer (261), and lung cancer (262) cell
lines, which are independent of the GH-releasing ef-
fect. In contrast, ghrelin may induce a proliferative
response in cell lines of hepatoma (263) and those of
prostate cancer in which IGF-1 and GH may have
tumorigenic potential (264). Since both ghrelin and
des-acyl ghrelin inhibit cell death in cardiomyocytes
and endothelial cells, acylation of the peptide is needed
for endocrine actions (42). These ndings indicate the
existence of additional receptor subtypes that may
exhibit different afnities for ghrelin/GHS and differ-
ent pathophysiological relevance (42, 254, 262, 265).
Ghrelin expression is reported in gastrointestinal
and pancreatic endocrine tumors and gastric neuroen-
docrine cell hyperplasia (53, 266). Ghrelin-producing
endocrine tumors may help in better understanding
ghrelin functions in humans and screening of circulat-
ing ghrelin levels for diagnostic work-up. Ghrelin may
also directly stimulate the differentiation of preadipo-
cytes and inhibit lipolysis, suggesting a role in the
process of adipogenesis (267). Ghrelin may increase
anxiety-like behavior and memory retention in rodents
(268, 269) and may be a sleep-promoting factor in
humans (270). Since the GHS receptor(s) is widely
distributed in the body, many other physiological ef-
fects of ghrelin may remain to be uncovered.
PERSPECTIVE
Ghrelin has illustrated the importance of functional
interdependency of the stomach and hypothalamus,
providing a crucial missing link in the regulation of
energy balance, growth, and the coordinated gastroin-
testinal function. The arcuate NPY/AgRP neurons may
act to sense and respond to a wide variety of hormone
and nutrient signals in the blood that are relevant to
both short- and long-term aspects of energy homeosta-
sis Eq. (7, 9, 11, 80) (Fig. 2). These diverse signals are
integrated and transmitted to motor centers such as
PVN, LHA, and brainstem to produce the coordinated
actions on feeding and associated autonomic, neuroen-
docrine, and gastrointestinal activities. Ghrelin may be
a counterpart to leptin and a key afferent component
in this system. Vagal pathways are deeply involved in
these diverse actions of ghrelin and other gastrointes-
tinal peptides.
Characterization of the gene encoding ghrelin and
its overall genomic structure has enabled genomic
screening of the ghrelin gene. Recent studies suggest
that Arg5lGln or Leu72Met polymorphism of pre-
proghrelin gene may be associated with lower plasma
ghrelin and insulin resistance or lower fat accumula-
tion (271, 272). However, Leu72Met polymorphism
may be associated with obesity in children and may
modulate glucose-induced insulin secretion (273, 274).
The nding that plasma ghrelin concentrations at
baseline are more alike within pairs of twins than
between pairs indicates a probable genetic effect un-
derlying the variability in plasma ghrelin levels (275).
Further studies are warranted to examine whether
genetic variation at ghrelin or its receptor locus could
be a genetic factor determining fat accumulation and
statural growth.
In the next few years, we foresee a rapid increase of
knowledge in such basic mechanisms in healthy and
diseased subjects, as well as in the diagnostic and
therapeutic uses of natural (ghrelin) and articial
GHSs. It will become apparent whether ghrelin is the
sole ligand or one of a number of ligands activating the
GHS receptor and whether GHS-RIa is the sole recep-
tor or one of a group of receptors for such ligands.
The discovery of ghrelin and approaches designed to
modulate the gastric neuroendocrine system open new
fascinating perspectives of research and therapeutic
potential on gastrointestinal, metabolic, endocrine,
and other various diseases.
The work was supported by grants from the Ministry of
Education, Science, Sports, and Culture of Japan.
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Received for publication July 30, 2003.
Accepted for publication November 13, 2003.

Ghrelin, Appetite, and Gastric Motility: The Emerging Role of The Stomach As An Endocrine Organ

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Ghrelin, Appetite, and Gastric Motility: The Emerging Role of The Stomach As An Endocrine Organ

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Ghrelin, appetite, and gastric motility: the emerging

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