2010 focus on the short- and long-term effects of ghrelin on energy
Nutrition 26 (2010) 579–584 Contents lists available at ScienceDirect Nutrition journal homepage: www.nutritionjrnl.comReviewFocus on the short- and long-term effects of ghrelin on energy homeostasisCarine 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, Belgiumb ´ Laboratory of Biological Chemistry and Nutrition, Universite Libre de Bruxelles, Brussels, Belgiuma r t i c l e i n f o a b s t r a c tArticle history: The endogenous ligand for the growth hormone secretagogue receptor, ghrelin, is a 28–amino-acidReceived 4 September 2009 peptide acylated with an octanoyl group at the serine in position 3. Most of the circulating ghrelinAccepted 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 highlyKeywords: pleiotropic hormone, contributing signiﬁcantly to the regulation of appetite and food intakeGhrelin control, gastrointestinal motility, gastric acid secretion, endocrine and exocrine pancreatic secre-Metabolism tions, cell proliferation, glucose and lipid metabolism, and cardiovascular and immunologicAppetite regulationEnergy 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-termligand for the growth hormone secretagogue receptor (GHS-R) regulation of food intake and long-term regulation of body. 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 thethe family of G-protein coupled receptor possessing seven treatment of obesity or cachexia are also presented.transmembrane helix domains . Des-acyl ghrelin and possiblyghrelin 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 increasesplasma consists of des-acyl-ghrelin . This could result from appetite and stimulates feeding [17,18]. Circulating ghrelin levelsa shorter half-life of ghrelin compared with des-acyl ghrelin , are increased by fasting and decreased by feeding, suggestingghrelin deacylation by butyrylcholinesterase, and platelet- a role of ghrelin in meal initiation [18,19]. In humans initiatingactivating factor acetylhydrolase [8,12]. Therefore, circulating meals voluntarily, without time- or food-related cues, theghrelin levels are difﬁcult to assess with accuracy and, conse- increase of ghrelin levels occurs before meals and showsquently, its physiologic and pathophysiologic roles. a similar temporal proﬁle with hunger scores . 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 ghrelinfunctions 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 suppressesand 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 MedicalScientiﬁc 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: email@example.com (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
580 C. De Vriese et al. / Nutrition 26 (2010) 579–584 Fig. 2. Intracellular mechanisms of the appetite-stimulating effect of ghrelin in theFig. 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, calmodulinagouti-related protein; ARC, arcuate nucleus; CART, cocaine- and amphetamine- kinase-kinase 2; CPT 1, carnitine-palmitoyltransferase-1; ROS, reactive oxygenregulated 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 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 thearcuate nucleus containing the orexigenic neurons expressing brain [49–52]. Ghrelin-induced feeding is indeed suppressedneuropeptide Y (NPY) and agouti-related protein (AGRP) and the when the vagal afferent pathway is blocked after vagotomy oranorexigenic neurons expressing pro-opiomelanocortin (POMC), the use of an afferent neurotoxin [53,54]. However, another studya-melanocyte–stimulating hormone (a-MSH), and cocaine- and rather has suggested that ghrelin action is not mediated by theamphetamine-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 deafferentationexpressing NPY and AGRP. Indeed, inhibition of endogenous NPY . However, Date et al.  showed that peripherally admin-and AGRP suppresses the orexigenic effect of ghrelin, as observed istered ghrelin transmits orexigenic signals to the nucleus tractusin 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 thestimulating effect of ghrelin in the hypothalamus have been NTS through a noradrenergic pathway. In contrast, ghrelin signalshown to involve the adenosine monophosphate–activated from the gut to the brain seems to be partially mediated by theprotein kinase (AMPK) [34,35] (Fig. 2). Through the increase of cholinergic ﬁbers of the vagus nerve .intracellular calcium induced by its binding to the GHS-R, ghrelinactivates calmodulin kinase-kinase 2 (CaMKK2), which phos-phorylates AMPK . AMPK phosphorylates and inhibits the Long-term effects of ghrelin on energy homeostasisacetyl-coenzyme A carboxylase (ACC), which inhibits theformation of malonyl-CoA and consequently activates carnitine- Body weight homeostasis is achieved when a balance existspalmitoyltransferase-1 (CPT1) . 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 intakegenerated and uncoupling protein-2 (UCP2) is stimulated, which and/or a relative increase in energy expenditure, whereas weightpromotes ROS scavenging and stimulates NPY/AGRP transcrip- gain would result from a relative increase in food intake and/ortion . Ghrelin’s effect on AMPK could be partially mediated a relative decrease in energy expenditure. Ghrelin induces bodyby cannabinoids [34,39]. Ghrelin also inhibits POMC neurons, weight gain and adiposity [57,58] by stimulating food intake,preventing the release of a-MSH  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 bodyand 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 healthyincreases food intake and stimulates dopamine release from the subjects with normal body weight [64–69]. Variations of bodyVTA [46,47]. Ghrelin also stimulates brain activity in areas weight lead to compensatory responses of ghrelin levels. Weightcontrolling appetitive behavior like the amygdala, orbitofrontal loss induced by food restriction and by long-term exercisecortex, anterior insula, and striatum . All these data strongly increases ghrelin levels [70–72]. However, weight loss inducedsuggest that, in addition to playing a role in the control of by gastric bypass surgery produce contradictory results in
C. De Vriese et al. / Nutrition 26 (2010) 579–584 581ghrelin levels: an increase [73–75], a decrease [67,76–78], or no increase body weight and may be an effective treatment forchange [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 PWSloss. Conversely, weight gain resulting from overfeeding, preg- [121–123]. In lean mice as in obese mice, ghrelin receptornancy, 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 developedsyndrome (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-loweringdecrease 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 highinsatiable 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 toGhrelin and GHS-R gene polymorphisms: Clinical anorexigenic hormones and preventing food intake betweenimplication 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]. Themosome 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 treatin the ghrelin gene, not counting the transcript and splice vari- diseases associated with high ghrelin levels such as PWS. RNAants. 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 andbut 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 activationdisorders and pathologies, such as various cancers, e.g., breast in the ARC but other fasting-related signals compensated the losscancer [100,101] and prostate cancer , and in obesity, of the ghrelin effect, explaining the rebound body weight gainshort stature, body weight, fat mass, and various eating disor- after several weeks of treatment . Another approach forders. In particular, the Leu72Met polymorphism in prepro- inhibiting endogenous ghrelin consists in an anti-ghrelin vaccineghrelin was associated with early onset of obesity [103–106] and using ghrelin hapten immuno-conjugates leading to thebinge eating disorder , whereas no association of Leu72Met production of antibodies speciﬁcally directed against acylatedand Arg-51-Gln could be found with anorexia nervosa or bulimia ghrelin. Vaccination against ghrelin decreases ghrelin levels andnervosa . In contrast, the Leu72Met/Gln90Leu haplotype body weight gain, with preferential reduction of fat masshad an excess transmission in patients with anorexia nervosa compared with lean mass, by reducing feed efﬁciency (weight. However, correlations in these various pathologies should gain per kilocalorie of food) . Moreover, an acyl-ghrelin–be taken with caution because conﬂicting results are present in speciﬁc neutralizing antibody inhibits appetite stimulated bythe current literature. Nevertheless, although there is contro- a transient surge in ghrelin levels. However, as for theversy as to the effects of ghrelin polymorphic variants on Spiegelmers, compensatory mechanisms contributing to thedifferent disorders and pathologies, one must also take into regulation of energy balance might explain the lack of long-termaccount the diversity of the subject panels used in the various effects of this antibody on body weight .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 inClinical applications of ghrelin vivo maintain greater whole-body energy expenditure during fasting and decrease subsequent refeeding in mice . The GHS-R agonists and antagonists have been developed to Furthermore, ghrelin O-acyl transferase, which octanoylatestreat 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 thetion of a variety of chronic diseases such as cancer, heart failure, deacylated form of ghrelin must be taken into account asand chronic kidney disease and is associated with increased a possible source of side effects due to an increased level of themortality. 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 theirappetite . In malnourished dialyzed patients, ghrelin Conclusions and outlookadministration enhances short-term food intake  and dailyghrelin treatment achieves a sustained positive change in energy The effects of ghrelin on short-term regulation of food intakebalance . This long-term effect of ghrelin on energy and long-term regulation of body weight have relatively beenhomeostasis 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 aslean body mass increased after 3 wk of treatment [115–117]. in obesity, will contribute to a better understanding of theirGhrelin agonists administered continuously to rats increased clinical implications. Clinical applications of ghrelin (GHS-Rbody weight gain by promoting fat mass and lean mass . 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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