Ghrelin is a peptide hormone that regulates energy homeostasis by stimulating appetite and food intake. It is secreted by the stomach and its levels rise before meals and in response to fasting. Ghrelin activates neurons in the hypothalamus that stimulate appetite and feeding behavior. It also acts on reward centers in the brain to influence food motivation. Long-term, ghrelin promotes weight gain by increasing food intake and fat storage while reducing energy expenditure. Polymorphisms in the ghrelin and ghrelin receptor genes have been linked to obesity and eating disorders. Ghrelin antagonists may help treat obesity by reducing appetite and food intake.

1. Nutrition 26 (2010) 579–584
Contents lists available at ScienceDirect
Nutrition
journal homepage: www.nutritionjrnl.com
Review
Focus on the short- and long-term effects of ghrelin on energy homeostasis
Carine De Vriese Ph.D. a, Jason Perret Ph.D. b, Christine Delporte Ph.D. b, *
a
´
Laboratory of Pharmaceutics and Biopharmaceutics, Universite Libre de Bruxelles, Brussels, Belgium
b
´
Laboratory of Biological Chemistry and Nutrition, Universite Libre de Bruxelles, Brussels, Belgium
a r t i c l e i n f o a b s t r a c t
Article history: The endogenous ligand for the growth hormone secretagogue receptor, ghrelin, is a 28–amino-acid
Received 4 September 2009 peptide acylated with an octanoyl group at the serine in position 3. Most of the circulating ghrelin
Accepted 17 September 2009 results from its synthesis and secretion by the X/A-like endocrine cells from the stomach and
proximal small intestine. Besides its potent growth hormone secretory action, ghrelin is a highly
Keywords: pleiotropic hormone, contributing significantly to the regulation of appetite and food intake
Ghrelin
control, gastrointestinal motility, gastric acid secretion, endocrine and exocrine pancreatic secre-
Metabolism
tions, cell proliferation, glucose and lipid metabolism, and cardiovascular and immunologic
Appetite regulation
Energy homeostasis processes. The purpose of this review is to consider the orexigenic effects of ghrelin on short-term
regulation of food intake and long-term regulation of body weight, the implications of genetic
ghrelin and growth hormone secretagogue receptor polymorphism, and the use of antagonists and
agonists of ghrelin in pathophysiological conditions.
Ó 2010 Elsevier Inc. All rights reserved.
Introduction and lipid metabolism, and cardiovascular and immunologic
processes [15,16].
Ghrelin was identified in the stomach as the endogenous In this review, we discuss the roles of ghrelin in short-term
ligand for the growth hormone secretagogue receptor (GHS-R) regulation of food intake and long-term regulation of body
[1]. Ghrelin is acylated by an octanoyl group at the serine in weight. The implications of genetic ghrelin and GHS-R poly-
position 3 by a ghrelin O-acyl transferase [2,3]. GHS-R belongs to morphism and the clinical applications of ghrelin in the
the family of G-protein coupled receptor possessing seven treatment of obesity or cachexia are also presented.
transmembrane helix domains [4]. Des-acyl ghrelin and possibly
ghrelin may also act on other as yet unidentified receptors [5–7]. Short-term effects of ghrelin on food intake
Ghrelin circulates into the bloodstream bound to lipoproteins
[8,9]. More than 90% of ghrelin immunoreactivity in the human In animals and in humans, ghrelin administration increases
plasma consists of des-acyl-ghrelin [10]. This could result from appetite and stimulates feeding [17,18]. Circulating ghrelin levels
a shorter half-life of ghrelin compared with des-acyl ghrelin [11], are increased by fasting and decreased by feeding, suggesting
ghrelin deacylation by butyrylcholinesterase, and platelet- a role of ghrelin in meal initiation [18,19]. In humans initiating
activating factor acetylhydrolase [8,12]. Therefore, circulating meals voluntarily, without time- or food-related cues, the
ghrelin levels are difficult to assess with accuracy and, conse- increase of ghrelin levels occurs before meals and shows
quently, its physiologic and pathophysiologic roles. a similar temporal profile with hunger scores [20]. Because the
Besides the stimulation of growth hormone release from the timing of ghrelin peaks is related to habitual meal patterns,
pituitary [13,14], ghrelin displays a wide spectrum of biological several studies have suggested that the preprandial ghrelin
functions such as the regulation of appetite and food intake, increase could anticipate eating rather than elicit feeding [21,22].
gastrointestinal motility, gastric acid secretion, endocrine Refeeding or gastric and enteric delivery of nutrients suppresses
and exocrine pancreatic secretions, cell proliferation, glucose circulating ghrelin levels. Moreover, composition of the diet
appears to strongly influence ghrelin secretion, with contradic-
tory results: a stronger decrease of ghrelin levels with proteins
This work was supported by grant 3.4561.07 from the Fund for Medical
Scientific Research (FNRS, Belgium).
and carbohydrates compared with lipids has been observed
* Corresponding author. Tel.: þ32-2-555-62-10; fax: þ32-2-555-62-30. [23,24], as has lower ghrelin levels after fat ingestion than after
E-mail address: cdelport@ulb.ac.be (C. Delporte). carbohydrate or protein ingestion [25,26]. However, Blom et al.
0899-9007/$ – see front matter Ó 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.nut.2009.09.013

2. 580 C. De Vriese et al. / Nutrition 26 (2010) 579–584
Fig. 2. Intracellular mechanisms of the appetite-stimulating effect of ghrelin in the
Fig. 1. Representation of the main brain pathways involved in the regulation of hypothalamus. þ, stimulates; À, inhibits; ACC, acetyl coenzyme A carboxylase;
food intake and feeding behavior by ghrelin. þ, stimulates; À, inhibits; AGRP, AMPK, adenosine monophosphate–activated protein kinase; CaMKK2, calmodulin
agouti-related protein; ARC, arcuate nucleus; CART, cocaine- and amphetamine- kinase-kinase 2; CPT 1, carnitine-palmitoyltransferase-1; ROS, reactive oxygen
regulated transcript; CRF, corticotropin-releasing factor; LHA, lateral hypothalamic species; UCP 2, uncoupling protein-2; Pi, phosphorylated state.
area; NPY, neuropeptide Y; NTS, nucleus of the solitary tract; POMC, pro-opiome-
lanocortin; PVN, paraventricular nucleus; VTA, ventral tegmental area.
appetite by hypothalamic circuits, ghrelin is implicated in the
[27] suggested that postprandial changes in ghrelin are corre- regulation of feeding behavior.
lated with the intermeal interval in normal-weight subjects only, In addition to stimulating appetite and food intake by orexi-
independent of diet. genic and anorexigenic pathways, ghrelin may stimulate appetite
Food intake is centrally controlled by the hypothalamic by the vagus nerve by mediating the signal from the gut to the
arcuate nucleus containing the orexigenic neurons expressing brain [49–52]. Ghrelin-induced feeding is indeed suppressed
neuropeptide Y (NPY) and agouti-related protein (AGRP) and the when the vagal afferent pathway is blocked after vagotomy or
anorexigenic neurons expressing pro-opiomelanocortin (POMC), the use of an afferent neurotoxin [53,54]. However, another study
a-melanocyte–stimulating hormone (a-MSH), and cocaine- and rather has suggested that ghrelin action is not mediated by the
amphetamine-regulated transcript (CART) [28–30] (Fig. 1). vagus nerve because intraperitoneal injection of ghrelin stimu-
Ghrelin-induced feeding results from the activation of neurons lates eating in rats with subdiaphragmatic vagal deafferentation
expressing NPY and AGRP. Indeed, inhibition of endogenous NPY [52]. However, Date et al. [55] showed that peripherally admin-
and AGRP suppresses the orexigenic effect of ghrelin, as observed istered ghrelin transmits orexigenic signals to the nucleus tractus
in NPY- and AGRP-null mice and after ablation of the NPY/AGRP solitarius (NTS), at least partially by the vagus nerve, and adja-
neurons [16,31–33]. Intracellular mechanisms of the appetite- cent to the hypothalamus by the ascending efferent fibers of the
stimulating effect of ghrelin in the hypothalamus have been NTS through a noradrenergic pathway. In contrast, ghrelin signal
shown to involve the adenosine monophosphate–activated from the gut to the brain seems to be partially mediated by the
protein kinase (AMPK) [34,35] (Fig. 2). Through the increase of cholinergic fibers of the vagus nerve [56].
intracellular calcium induced by its binding to the GHS-R, ghrelin
activates calmodulin kinase-kinase 2 (CaMKK2), which phos-
phorylates AMPK [36]. AMPK phosphorylates and inhibits the Long-term effects of ghrelin on energy homeostasis
acetyl-coenzyme A carboxylase (ACC), which inhibits the
formation of malonyl-CoA and consequently activates carnitine- Body weight homeostasis is achieved when a balance exists
palmitoyltransferase-1 (CPT1) [37]. With the resulting increased between food intake and energy expenditure. As a consequence,
mitochondrial b-oxidation, reactive oxygen species (ROS) are weight loss would result from a relative decrease in food intake
generated and uncoupling protein-2 (UCP2) is stimulated, which and/or a relative increase in energy expenditure, whereas weight
promotes ROS scavenging and stimulates NPY/AGRP transcrip- gain would result from a relative increase in food intake and/or
tion [38]. Ghrelin’s effect on AMPK could be partially mediated a relative decrease in energy expenditure. Ghrelin induces body
by cannabinoids [34,39]. Ghrelin also inhibits POMC neurons, weight gain and adiposity [57,58] by stimulating food intake,
preventing the release of a-MSH [40] and activates neurons with a preference for fat ingestion, promoting fat storage,
expressing orexin in the lateral hypothalamic area [41–43]. reducing energy expenditure and fat utilization, and increasing
Recent studies have suggested that ghrelin acts on two carbohydrate utilization [59–63].
dopaminergic regions of the mesolimbic system, the striatum Plasma ghrelin levels are negatively correlated with body
and ventral tegmental area (VTA), which are involved in reward mass index. Indeed, patients with obesity and anorexia have,
perception [44,45]. Administration of ghrelin into the VTA respectively, lower and higher plasma ghrelin levels than healthy
increases food intake and stimulates dopamine release from the subjects with normal body weight [64–69]. Variations of body
VTA [46,47]. Ghrelin also stimulates brain activity in areas weight lead to compensatory responses of ghrelin levels. Weight
controlling appetitive behavior like the amygdala, orbitofrontal loss induced by food restriction and by long-term exercise
cortex, anterior insula, and striatum [48]. All these data strongly increases ghrelin levels [70–72]. However, weight loss induced
suggest that, in addition to playing a role in the control of by gastric bypass surgery produce contradictory results in

3. C. De Vriese et al. / Nutrition 26 (2010) 579–584 581
ghrelin levels: an increase [73–75], a decrease [67,76–78], or no increase body weight and may be an effective treatment for
change [79–82]. This variability could be explained by the cachexia [119,120].
differences in surgical techniques used, and by the differences in The GHS-R-1a antagonists might be beneficial for the treat-
patients attaining a stable body mass index or pursuing weight ment of type 2 diabetes and obesity and particularly for PWS
loss. Conversely, weight gain resulting from overfeeding, preg- [121–123]. In lean mice as in obese mice, ghrelin receptor
nancy, olanzapine treatment, and high-fat diet decreases ghrelin antagonists decrease food intake and reduce weight gain.
levels [83–88]. However, obese patients with Prader-Willi Recently, orally bioavailable antagonists have been developed
syndrome (PWS) present higher plasma ghrelin levels than and lead to suppression of food intake and body weight reduc-
healthy subjects. These levels do not decrease after a meal or tion through selective loss of fat mass and glucose-lowering
decrease to a lesser extent than in obese and lean subjects, effects by enhancing insulin secretion [123,124].
suggesting that ghrelin may contribute, at least partially, to the The inverse agonist of GHS-R-1a, decreasing the high
insatiable appetite and obesity of these patients [89–94]. constitutive activity of the ghrelin receptor, might be useful for
the treatment of obesity by increasing the sensitivity to
Ghrelin and GHS-R gene polymorphisms: Clinical anorexigenic hormones and preventing food intake between
implication meals [125–127]. However, humans with mutations of GHS-R-1a,
leading to a lack of constitutive activity of the receptor, present
Ghrelin and its receptor (GHSR) genes are located on chro- a short stature but are also subject to obesity [128,129]. The
mosome 3. The ghrelin gene yields a complex array of transcripts utility of inverse agonists in the treatment of obesity therefore
[95,96] and may yield a series of other non-ghrelin peptides needs to be investigated further.
[97–99]. A large number of polymorphisms have been identified Neutralization of circulating ghrelin could be useful to treat
in the ghrelin gene, not counting the transcript and splice vari- diseases associated with high ghrelin levels such as PWS. RNA
ants. Several are found in the coding region of ghrelin; however, Spiegelmers, antisense polyethylene glycol-modified L-oligonu-
a large number are in non-coding regions or in prepro-ghrelin cleotides that specifically bind ghrelin, decrease food intake and
but outside the ghrelin coding region. Polymorphisms of ghrelin body weight in diet-induced obese mice [121,130–132]. Spie-
and its receptor GHSR-1a have been studied in a wide series of gelmer NOX-B11-3 blocked ghrelin-induced neuronal activation
disorders and pathologies, such as various cancers, e.g., breast in the ARC but other fasting-related signals compensated the loss
cancer [100,101] and prostate cancer [102], and in obesity, of the ghrelin effect, explaining the rebound body weight gain
short stature, body weight, fat mass, and various eating disor- after several weeks of treatment [133]. Another approach for
ders. In particular, the Leu72Met polymorphism in prepro- inhibiting endogenous ghrelin consists in an anti-ghrelin vaccine
ghrelin was associated with early onset of obesity [103–106] and using ghrelin hapten immuno-conjugates leading to the
binge eating disorder [107], whereas no association of Leu72Met production of antibodies specifically directed against acylated
and Arg-51-Gln could be found with anorexia nervosa or bulimia ghrelin. Vaccination against ghrelin decreases ghrelin levels and
nervosa [108]. In contrast, the Leu72Met/Gln90Leu haplotype body weight gain, with preferential reduction of fat mass
had an excess transmission in patients with anorexia nervosa compared with lean mass, by reducing feed efficiency (weight
[109]. However, correlations in these various pathologies should gain per kilocalorie of food) [134]. Moreover, an acyl-ghrelin–
be taken with caution because conflicting results are present in specific neutralizing antibody inhibits appetite stimulated by
the current literature. Nevertheless, although there is contro- a transient surge in ghrelin levels. However, as for the
versy as to the effects of ghrelin polymorphic variants on Spiegelmers, compensatory mechanisms contributing to the
different disorders and pathologies, one must also take into regulation of energy balance might explain the lack of long-term
account the diversity of the subject panels used in the various effects of this antibody on body weight [135].
studies, the series of polymorphisms investigated, and the ethnic Ghrelin degradation by antibodies might also be therapeuti-
and international variations in ghrelin gene polymorphism. cally relevant to PWS. Antibodies hydrolyzing the serine octa-
noate ester moiety of ghrelin-modulated energy homeostasis in
Clinical applications of ghrelin vivo maintain greater whole-body energy expenditure during
fasting and decrease subsequent refeeding in mice [136].
The GHS-R agonists and antagonists have been developed to Furthermore, ghrelin O-acyl transferase, which octanoylates
treat cachexia and obesity, respectively. Cachexia is a syndrome ghrelin, might represent an additional interesting pharmaceu-
of physical wasting that involves the loss of fat and protein stores tical target for the development of specific inhibitors. However,
leading to weight loss and decrease of appetite. It is a complica- the growing body of evidence indicating a potential role for the
tion of a variety of chronic diseases such as cancer, heart failure, deacylated form of ghrelin must be taken into account as
and chronic kidney disease and is associated with increased a possible source of side effects due to an increased level of the
mortality. Although ghrelin levels are increased in underweight deacylated form after the latter therapeutic approach.
patients with cachexia or anorexia [110,111], ghrelin adminis-
tration to cachectic patients with cancer has improved their
appetite [112]. In malnourished dialyzed patients, ghrelin Conclusions and outlook
administration enhances short-term food intake [113] and daily
ghrelin treatment achieves a sustained positive change in energy The effects of ghrelin on short-term regulation of food intake
balance [114]. This long-term effect of ghrelin on energy and long-term regulation of body weight have relatively been
homeostasis has been shown also in patients with heart failure well documented. Further studies on ghrelin and GHS-R poly-
and with chronic obstructive pulmonary disease, because their morphisms, shown to be implicated in several disorders such as
lean body mass increased after 3 wk of treatment [115–117]. in obesity, will contribute to a better understanding of their
Ghrelin agonists administered continuously to rats increased clinical implications. Clinical applications of ghrelin (GHS-R
body weight gain by promoting fat mass and lean mass [118]. An agonists and antagonists, RNA Spiegelmers, antibodies anti-
orally active ghrelin agonist, tested in healthy subjects, seems to ghrelin, ghrelin O-acyl transferase inhibitors) are being currently

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