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: firstname.lastname@example.org (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
582 C. De Vriese et al. / Nutrition 26 (2010) 579–584investigated, but certainly will require much further  Beck B, Max JP, Fernette B, Richy S. Adaptation of ghrelin levels to limit body weight gain in the obese Zucker rat. Biochem Biophys Res Communinvestigation. 2004;318:846–51.  Blom WA, de Graaf C, Lluch A, Staﬂeu A, Schaafsma G, Hendriks HF. Postprandial ghrelin responses are associated with the intermeal intervalReferences in time-blinded normal weight men, but not in obese men. Physiol Behav 2009;96:742–8.  Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is  Huda MSB, Wilding JPH, Pinkney JH. Gut peptides and the regulation of a growth-hormone–releasing acylated peptide from stomach. Nature appetite. Obes Rev 2006;7:163–82. 1999;402:656–60.  Abizaid A, Horvath TL. Brain circuits regulating energy homeostasis. Regul  Gutierrez JA, Solenberg PJ, Perkins DR, Willency JA, Knierman MD, Jin Z, Pept 2008;149:3–10. et al. Ghrelin octanoylation mediated by an orphan lipid transferase 5.  Shioda S, Takenoya F, Yagi M, Wang L, Hori Y, Kageyama H. Neural Proc Natl Acad Sci U S A 2008;105:6320–5. networks of several novel neuropeptides involved in feeding regulation.  Yang J, Brown MS, Liang G, Grishin NV, Goldstein JL. Identiﬁcation of the Nutrition 2008;24:848–53. acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide  Chen HY, Trumbauer ME, Chen AS, Weingarth DT, Adams JR, Frazier EG, hormone. Cell 2008;132:387–96. et al. Orexigenic action of peripheral ghrelin is mediated by neuropeptide  Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, Y and agouti-related protein. Endocrinology 2004;145:2607–12. et al. A receptor in pituitary and hypothalamus that functions in growth  Coiro V, Saccani-Jotti G, Rubino P, Manfredi G, Melani A, Chiodera P. hormone release. Science 1996;273:974–7. Effects of ghrelin on circulating neuropeptide Y levels in humans. Neurol  De Vriese C, Delporte C. Autocrine proliferative effect of ghrelin on Endocrinol Lett 2006;27:755–7. leukemic HL-60 and THP-1 cells. J Endocrinol 2007;192:199–205.  Luquet S, Phillips CT, Palmiter RD. NPY/AgRP neurons are not essential for  De Vriese C, Gregoire F, De Neef P, Robberecht P, Delporte C. Ghrelin is feeding responses to glucoprivation. Peptides 2007;28:214–25. produced by the human erythroleukemic HEL cell line and involved in an  Kola B, Hubina E, Tucci SA, Kirkham TC, Garcia EA, Mitchell SE, et al. autocrine pathway leading to cell proliferation. Endocrinology Cannabinoids and ghrelin have both central and peripheral metabolic and 2005;146:1514–22. cardiac effects via AMP-activated protein kinase. J Biol Chem  Ghigo E, Broglio F, Arvat E, Maccario M, Papotti M, Muccioli G. Ghrelin: 2005;280:25196–201. more than a natural GH secretagogue and/or an orexigenic factor. Clin  Kola B, Korbonits M. Shedding light on the intricate puzzle of ghrelin’s Endocrinol (Oxf) 2005;62:1–17. effects on appetite regulation. J Endocrinol 2009;202:191–8.  De Vriese C, Hacquebard M, Gregoire F, Carpentier Y, Delporte C. Ghrelin  Anderson KA, Ribar TJ, Lin F, Noeldner PK, Green MF, Muehlbauer MJ, et al. interacts with human plasma lipoproteins. Endocrinology 2007;148: Hypothalamic CaMKK2 contributes to the regulation of energy balance. 2355–62. Cell Metab 2008;7:377–88.  Beaumont NJ, Skinner VO, Tan TM, Ramesh BS, Byrne DJ, MacColl GS, et al.  Lopez M, Lage R, Saha AK, Perez-Tilve D, Vazquez MJ, Varela L, et al. Ghrelin can bind to a species of high density lipoprotein associated with Hypothalamic fatty acid metabolism mediates the orexigenic action of paraoxonase. J Biol Chem 2003;278:8877–80. ghrelin. Cell Metab 2008;7:389–99. Patterson M, Murphy KG, le Roux CW, Ghatei MA, Bloom SR. Character-  Andrews ZB, Liu ZW, Walllingford N, Erion DM, Borok E, Friedman JM, ization of ghrelin-like immunoreactivity in human plasma. J Clin Endo- et al. UCP2 mediates ghrelin’s action on NPY/AgRP neurons by lowering crinol Metab 2005;90:2205–11. free radicals. Nature 2008;454:846–51. Akamizu T, Shinomiya T, Irako T, Fukunaga M, Nakai Y, Nakai Y, Kangawa K.  Kola B, Farkas I, Christ-Crain M, Wittmann G, Lolli F, Amin F, et al. The Separate measurement of plasma levels of acylated and desacyl ghrelin in orexigenic effect of ghrelin is mediated through central activation of the healthy subjects using a new direct ELISA assay. J Clin Endocrinol Metab endogenous cannabinoid system. PLoS One 2008;3:e1797. 2005;90:6–9.  Riediger T, Traebert M, Schmid HA, Scheel C, Lutz TA, Scharrer E. Site- De Vriese C, Gregoire F, Lema-Kisoka R, Waelbroeck M, Robberecht P, speciﬁc effects of ghrelin on the neuronal activity in the hypothalamic Delporte C. Ghrelin degradation by serum and tissue homogenates: arcuate nucleus. Neurosci Lett 2003;341:151–5. identiﬁcation of the cleavage sites. Endocrinology 2004;145:4997–5005.  Scott V, Mcdade DM, Luckman SM. Rapid changes in the sensitivity of Takaya K, Ariyasu H, Kanamoto N, Iwakura H, Yoshimoto A, Harada M, arcuate nucleus neurons to central ghrelin in relation to feeding status. et al. Ghrelin strongly stimulates growth hormone release in humans. Physiol Behav 2007;90:180–5. J Clin Endocrinol Metab 2000;85:4908–11.  Yamanaka A, Beuckmann CT, Willie JT, Hara J, Tsujino N, Mieda M, et al. Date Y, Murakami N, Kojima M, Kuroiwa T, Matsukura S, Kangawa K, Hypothalamic orexin neurons regulate arousal according to energy Nakazato M. Central effects of a novel acylated peptide, ghrelin, on growth balance in mice. Neuron 2003;38:701–13. hormone release in rats. Biochem Biophys Res Commun 2000;275:477–80.  Toshinai K, Date Y, Murakami N, Shimada M, Mondal MS, Shimbara T, et al. De Vriese C, Delporte C. Ghrelin: a new peptide regulating growth Ghrelin-induced food intake is mediated via the orexin pathway. hormone release and food intake. Int J Biochem Cell Biol 2008;40:1420–4. Endocrinology 2003;144:1506–12. Soares JB, Leite-Moreira AF. Ghrelin, des-acyl ghrelin and obestatin: three  Jerlhag E. Systemic administration of ghrelin induces conditioned pieces of the same puzzle. Peptides 2008;29:1255–70. place preference and stimulates accumbal dopamine. Addict Biol Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, 2008;13:358–63. Matsukura S. A role for ghrelin in the central regulation of feeding. Nature  Naleid AM, Grace MK, Cummings DE, Levine AS. Ghrelin induces feeding 2001;409:194–8. in the mesolimbic reward pathway between the ventral tegmental area Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, et al. and the nucleus accumbens. Peptides 2005;26:2274–9. Ghrelin enhances appetite and increases food intake in humans. J Clin  Jerlhag E, Egecioglu E, Dickson SL, Douhan A, Svensson L, Engel JA. Ghrelin Endocrinol Metab 2001;86:5992–5. administration into tegmental areas stimulates locomotor activity and Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS. A increases extracellular concentration of dopamine in the nucleus preprandial rise in plasma ghrelin levels suggests a role in meal initiation accumbens. Addict Biol 2007;12:6–16. in humans. Diabetes 2001;50:1714–9.  Abizaid A. Ghrelin and dopamine: new insights on the peripheral regu- Cummings DE, Frayo RS, Marmonier C, Aubert R, Chapelot D. Plasma lation of appetite. J Neuroendocrinol 2009;21:787–93. ghrelin levels and hunger scores in humans initiating meals voluntarily  Malik S, McGlone F, Bedrossian D, Dagher A. Ghrelin modulates brain without time- and food-related cues. Am J Physiol Endocrinol Metab activity in areas that control appetitive behavior. Cell Metab 2008;7:400–9. 2004;287:E297–304.  Sakata I, Yamazaki M, Inoue K, Hayashi Y, Kangawa K, Sakai T. Growth Frecka JM, Mattes RD. Possible entrainment of ghrelin to habitual meal hormone secretagogue receptor expression in the cells of the stomach- patterns in humans. Am J Physiol Gastrointest Liver Physiol projected afferent nerve in the rat nodose ganglion. Neurosci Lett 2008;294:G699–707. 2003;342:183–6. Drazen DL, Vahl TP, D’Alessio DA, Seeley RJ, Woods SC. Effects of a ﬁxed  Burdyga G, Varro A, Dimaline R, Thompson DG, Dockray GJ. Ghrelin meal pattern on ghrelin secretion: evidence for a learned response receptors in rat and human nodose ganglia: putative role in regulating independent of nutrient status. Endocrinology 2006;147:23–30. CB-1 and MCH receptor abundance. Am J Physiol Gastrointest Liver Overduin J, Frayo RS, Grill HJ, Kaplan JM, Cummings DE. Role of the Physiol 2006;290:G1289–97. duodenum and macronutrient type in ghrelin regulation. Endocrinology  Date Y, Murakami N, Toshinai K, Matsukura S, Niijima A, Matsuo H, et al. 2005;146:845–50. The role of the gastric afferent vagal nerve in ghrelin-induced feeding and Foster-Schubert KE, Overduin J, Prudom CE, Liu J, Callahan HS, Gaylinn BD. growth hormone secretion in rats. Gastroenterology 2002;123:1120–8. e al. Acyl and total ghrelin are suppressed strongly by ingested proteins,  Arnold M, Mura A, Langhans W, Geary N. Gut vagal afferents are not weakly by lipids, and biphasically by carbohydrates. J Clin Endocrinol necessary for the eating-stimulatory effect of intraperitoneally injected Metab 2008;93:1971–9. ghrelin in the rat. J Neurosci 2006;26:11052–60. Beck B, Richy S. Differential long-term dietary regulation of adipokines,  Date Y, Murakami N, Toshinai K, Matsukura S, Niijima A, Matsuo H, et al. ghrelin, or corticosterone: impact on adiposity. J Endocrinol The role of the gastric afferent vagal nerve in ghrelin-induced feeding and 2008;196:171–9. growth hormone secretion in rats. Gastroenterology 2002;123:1120–8.
C. De Vriese et al. / Nutrition 26 (2010) 579–584 583 le Roux CW, Neary NM, Halsey TJ, Small CJ, Martinez-Isla AM, Ghatei MA,  Stenstrom B, Zhao CM, Tommeras K, Arum CJ, Chen D. Is gastrin partially et al. Ghrelin does not stimulate food intake in patients with surgical responsible for body weight reduction after gastric bypass? Eur Surg Res procedures involving vagotomy. J Clin Endocrinol Metab 2005;90:4521–4. 2006;38:94–101. Date Y, Shimbara T, Koda S, Toshinai K, Ida T, Murakami N, et al. Peripheral  Mancini MC, Costa AP, de Melo ME, Cercato C, Giannella-Neto D, ghrelin transmits orexigenic signals through the noradrenergic pathway Garrido Jr AB, et al. Effect of gastric bypass on spontaneous growth from the hindbrain to the hypothalamus. Cell Metab 2006;4:323–31. hormone and ghrelin release proﬁles. Obesity (Silver Spring) Maier C, Riedl M, Vila G, Nowotny P, Wolzt M, Clodi M, et al. Cholinergic 2006;14:383–7. regulation of ghrelin and peptide YY release may be impaired in obesity.  Olivan B, Teixeira J, Bose M, Bawa B, Chang T, Summe H, et al. Effect of Diabetes 2008;57:2332–40. weight loss by diet or gastric bypass surgery on peptide YY3–36 levels. Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Ann Surg 2009;249:948–53. Nature 2000;407:908–13.  Ybarra J, Bobbioni-Harsch E, Chassot G, Huber O, Morel P, Assim- Tsubone T, Masaki T, Katsuragi I, Tanaka K, Kakuma T, Yoshimatsu H. acopoulos-Jeannet F, Golay A. Persistent correlation of ghrelin plasma Ghrelin regulates adiposity in white adipose tissue and UCP1 levels with body mass index both in stable weight conditions and during mRNA expression in brown adipose tissue in mice. Regul Pept gastric-bypass-induced weight loss. Obes Surg 2009;19:327–31. 2005;130:97–103.  Williams DL, Grill HJ, Cummings DE, Kaplan JM. Overfeeding-induced Wortley KE, Anderson KD, Garcia K, Murray JD, Malinova L, Liu R, et al. weight gain suppresses plasma ghrelin levels in rats. J Endocrinol Invest Genetic deletion of ghrelin does not decrease food intake but inﬂuences 2006;29:863–8. metabolic fuel preference. Proc Natl Acad Sci U S A 2004;101:8227–32.  Palik E, Baranyi E, Melczer Z, Audikovszky M, Szocs A, Winkler G, Cseh K. Pﬂuger PT, Kirchner H, Gunnel S, Schrott B, Perez-Tilve D, Fu S, et al. Elevated serum acylated (biologically active) ghrelin and resistin levels Simultaneous deletion of ghrelin and its receptor increases motor activity associate with pregnancy-induced weight gain and insulin resistance. and energy expenditure. Am J Physiol Gastrointest Liver Physiol Diabetes Res Clin Pract 2007;76:351–7. 2008;294:G610–8.  Hosojima H, Togo T, Odawara T, Hasegawa K, Miura S, Kato Y, et al. Early Thompson NM, Gill DA, Davies R, Loveridge N, Houston PA, Robinson IC, effects of olanzapine on serum levels of ghrelin, adiponectin and leptin in Wells T. Ghrelin and des-octanoyl ghrelin promote adipogenesis directly patients with schizophrenia. J Psychopharmacol 2006;20:75–9. in vivo by a mechanism independent of the type 1a growth hormone  Otukonyong EE, Dube MG, Torto R, Kalra PS, Kalra SP. High-fat diet- secretagogue receptor. Endocrinology 2004;145:234–42. induced ultradian leptin and insulin hypersecretion are absent in obesity- Kim SW, Her SJ, Park SJ, Kim D, Park KS, Lee HK, et al. Ghrelin stimulates resistant rats. Obes Res 2005;13:991–9. proliferation and differentiation and inhibits apoptosis in osteoblastic  Kim BJ, Sohn JW, Park CS, Hahn GH, Koo J, Noh YD, Lee CS. Body weight MC3T3-E1 cells. Bone 2005;37:359–69. and plasma levels of ghrelin and leptin during treatment with olanzapine. Shimbara T, Mondal MS, Kawagoe T, Toshinai K, Koda S, Yamaguchi H, J Korean Med Sci 2008;23:685–90. et al. Central administration of ghrelin preferentially enhances fat inges-  Perez-Iglesias R, Vazquez-Barquero JL, Amado JA, Berja A, Garcia- tion. Neurosci Lett 2004;369:75–9. Unzueta MT, Pelayo-Teran JM, et al. Effect of antipsychotics on peptides Soriano-Guillen L, Barrios V, Campos-Barros A, Argente J. Ghrelin levels in involved in energy balance in drug-naive psychotic patients after 1 year of obesity and anorexia nervosa: effect of weight reduction or recuperation. treatment. J Clin Psychopharmacol 2008;28:289–95. J Pediatr 2004;144:36–42.  Cummings DE, Clement K, Purnell JQ, Vaisse C, Foster KE, Frayo RS, et al. Purnell JQ, Cummings D, Weigle DS. Changes in 24-h area-under-the- Elevated plasma ghrelin levels in Prader Willi syndrome. Nat Med curve ghrelin values following diet-induced weight loss are associated 2002;8:643–4. with loss of fat-free mass, but not with changes in fat mass, insulin levels  DelParigi A, Tschop M, Heiman ML, Salbe AD, Vozarova B, Sell SM, et al. or insulin sensitivity. Int J Obes (Lond) 2007;31:385–9. High circulating ghrelin: a potential cause for hyperphagia and obesity in Nagaya N, Uematsu M, Kojima M, Date Y, Nakazato M, Okumura H, et al. Prader-Willi syndrome. J Clin Endocrinol Metab 2002;87:5461–4. Elevated circulating level of ghrelin in cachexia associated with chronic  Gimenez-Palop O, Gimenez-Perez G, Mauricio D, Gonzalez-Clemente JM, heart failure: relationships between ghrelin and anabolic/catabolic Potau N, Berlanga E, et al. A lesser postprandial suppression of plasma factors. Circulation 2001;104:2034–8. ghrelin in Prader-Willi syndrome is associated with low fasting Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, and a blunted postprandial PYY response. Clin Endocrinol (Oxf) Purnell JQ. Plasma ghrelin levels after diet-induced weight loss or gastric 2007;66:198–204. bypass surgery. N Engl J Med 2002;346:1623–30.  Erdie-Lalena CR, Holm VA, Kelly PC, Frayo RS, Cummings DE. Ghrelin De Vriese C, Delporte C. Inﬂuence of ghrelin on food intake and energy levels in young children with Prader-Willi syndrome. J Pediatr homeostasis. Curr Opin Clin Nutr Metab Care 2007;10:615–9. 2006;149:199–204. Shiiya T, Nakazato M, Mizuta M, Date Y, Mondal MS, Tanaka M, et al.  Haqq AM, Farooqi IS, O’Rahilly S, Stadler DD, Rosenfeld RG, Pratt KL, et al. Plasma ghrelin levels in lean and obese humans and the effect of glucose Serum ghrelin levels are inversely correlated with body mass index, age, on ghrelin secretion. J Clin Endocrinol Metab 2002;87:240–4. and insulin concentrations in normal children and are markedly increased Purnell JQ, Cummings D, Weigle DS. Changes in 24-h area-under-the- in Prader-Willi syndrome. J Clin Endocrinol Metab 2003;88:174–8. curve ghrelin values following diet-induced weight loss are associated  Haqq AM, Grambow SC, Muehlbauer M, Newgard CB, Svetkey LP, with loss of fat-free mass, but not with changes in fat mass, insulin levels Carrel AL, et al. Ghrelin concentrations in Prader-Willi syndrome (PWS) or insulin sensitivity. Int J Obes (Lond) 2007;31:385–9. infants and children: changes during development. Clin Endocrinol (Oxf) Kraemer RR, Castracane VD. Exercise and humoral mediators of peripheral 2008;69:911–20. energy balance: ghrelin and adiponectin. Exp Biol Med (Maywood)  Seim I, Carter SL, Herington AC, Chopin LK. Complex organisation and 2007;232:184–94. structure of the ghrelin antisense strand gene GHRLOS, a candidate non- Beck B, Richy S. Dietary modulation of ghrelin and leptin and gorging coding RNA gene. BMC Mol Biol 2008;9:95. behavior after weight loss in the obese Zucker rat. J Endocrinol  Seim I, Herington AC, Chopin LK. New insights into the molecular 2009;202:29–34. complexity of the ghrelin gene locus. Cytokine Growth Factor Rev Stratis C, Alexandrides T, Vagenas K, Kalfarentzos F. Ghrelin and peptide 2009;20:297–304. YY levels after a variant of biliopancreatic diversion with Roux-en-Y  Seim I, Amorim L, Walpole C, Carter S, Chopin LK, Herington AC. Ghrelin gastric bypass versus after colectomy: a prospective comparative study. gene-related peptides: multi-functional endocrine/autocrine modulators Obes Surg 2006;16:752–8. in health and disease. Clin Exp Pharmacol Physiol 2009. Epub ahead of Mingrone G, Granato L, Valera-Mora E, Iaconelli A, Calvani MF, Bracaglia R, print. et al. Ultradian ghrelin pulsatility is disrupted in morbidly obese subjects  Soares JB, Leite-Moreira AF. Ghrelin, des-acyl ghrelin and obestatin: three after weight loss induced by malabsorptive bariatric surgery. Am J Clin pieces of the same puzzle 2. Peptides 2008;29:1255–70. Nutr 2006;83:1017–24.  Zhang JV, Ren PG, Avsian-Kretchmer O, Luo CW, Rauch R, Klein C, Holdstock C, Engstrom BE, Ohrvall M, Lind L, Sundbom M, Karlsson FA. Hsueh AJ. Obestatin, a peptide encoded by the ghrelin gene, opposes Ghrelin and adipose tissue regulatory peptides: effect of gastric bypass ghrelin’s effects on food intake. Science 2005;310:996–9. surgery in obese humans. J Clin Endocrinol Metab 2003;88:3177–83.  Dossus L, McKay JD, Canzian F, Wilkening S, Rinaldi S, Biessy C, et al. Fruhbeck G, Rotellar F, Hernandez-Lizoain JL, Gil MJ, Gomez-Ambrosi J, Polymorphisms of genes coding for ghrelin and its receptor in relation to Salvador J, Cienfuegos JA. Fasting plasma ghrelin concentrations 6 months anthropometry, circulating levels of IGF-I and IGFBP-3, and breast cancer after gastric bypass are not determined by weight loss or changes in risk: a case-control study nested within the European Prospective insulinemia. Obes Surg 2004;14:1208–15. Investigation into Cancer and Nutrition (EPIC). Carcinogenesis Langer FB, Reza Hoda MA, Bohdjalian A, Felberbauer FX, Zacherl J, 2008;29:1360–6. Wenzl E, et al. Sleeve gastrectomy and gastric banding: effects on plasma  Jeffery PL, Murray RE, Yeh AH, McNamara JF, Duncan RP, Francis GD, et al. ghrelin levels. Obes Surg 2005;15:1024–9. Expression and function of the ghrelin axis, including a novel pre- Roth CL, Reinehr T, Schernthaner GH, Kopp HP, Kriwanek S, proghrelin isoform, in human breast cancer tissues and cell lines. Endocr Schernthaner G. Ghrelin and obestatin levels in severely obese women Relat Cancer 2005;12:839–50. before and after weight loss after Roux-en-Y gastric bypass surgery. Obes  Yeh AH, Jeffery PL, Duncan RP, Herington AC, Chopin LK. Ghrelin and Surg 2009;19:29–35. a novel preproghrelin isoform are highly expressed in prostate cancer and
584 C. De Vriese et al. / Nutrition 26 (2010) 579–584 ghrelin activates mitogen-activated protein kinase in prostate cancer. Clin  Garcia JM, Polvino WJ. Pharmacodynamic hormonal effects of anamorelin, Cancer Res 2005;11:8295–303. a novel oral ghrelin mimetic and growth hormone secretagogue in healthy Korbonits M, Gueorguiev M, O’Grady E, Lecoeur C, Swan DC, Mein CA, volunteers. Growth Horm IGF Res 2009;19:267–73. et al. A variation in the ghrelin gene increases weight and decreases  Garcia JM, Polvino WJ. Effect on body weight and safety of RC-1291, insulin secretion in tall, obese children. J Clin Endocrinol Metab a novel, orally available ghrelin mimetic and growth hormone secreta- 2002;87:4005–8. gogue: results of a phase I, randomized, placebo-controlled, multiple- Miraglia dGSantoro N, Cirillo G, Raimondo P, Grandone A, D’Aniello A, dose study in healthy volunteers. Oncologist 2007;12:594–600. et al. Molecular screening of the ghrelin gene in Italian obese children: the  Asakawa A, Inui A, Kaga T, Katsuura G, Fujimiya M, Fujino MA, Kasuga M. Leu72Met variant is associated with an earlier onset of obesity. Int J Obes Antagonism of ghrelin receptor reduces food intake and body weight gain Relat Metab Disord 2004;28:447–50. in mice. Gut 2003;52:947–52. Ukkola O, Ravussin E, Jacobson P, Snyder EE, Chagnon M, Sjostrom L,  Beck B, Richy S, Stricker-Krongrad A. Feeding response to ghrelin agonist Bouchard C. Mutations in the preproghrelin/ghrelin gene associated with and antagonist in lean and obese Zucker rats. Life Sci 2004;76:473–8. obesity in humans. J Clin Endocrinol Metab 2001;86:3996–9.  Esler WP, Rudolph J, Claus TH, Tang W, Barucci N, Brown SE, et al. Small- Ukkola O, Ravussin E, Jacobson P, Perusse L, Rankinen T, Tschop M, et al. molecule ghrelin receptor antagonists improve glucose tolerance, Role of ghrelin polymorphisms in obesity based on three different studies. suppress appetite, and promote weight loss. Endocrinology Obes Res 2002;10:782–91. 2007;148:5175–85. Monteleone P, Tortorella A, Castaldo E, Di Filippo C, Maj M. The Leu72Met  Rudolph J, Esler WP, O’Connor S, Coish PD, Wickens PL, Brands M, et al. polymorphism of the ghrelin gene is signiﬁcantly associated with binge Quinazolinone derivatives as orally available ghrelin receptor antagonists eating disorder. Psychiatr Genet 2007;17:13–6. for the treatment of diabetes and obesity. J Med Chem 2007;50:5202–16. Monteleone P, Tortorella A, Castaldo E, Di Filippo C, Maj M. No association  Holst B, Cygankiewicz A, Jensen TH, Ankersen M, Schwartz TW. High of the Arg51Gln and Leu72Met polymorphisms of the ghrelin gene with constitutive signaling of the ghrelin receptordidentiﬁcation of a potent anorexia nervosa or bulimia nervosa. Neurosci Lett 2006;398:325–7. inverse agonist. Mol Endocrinol 2003;17:2201–10. Dardennes RM, Zizzari P, Tolle V, Foulon C, Kipman A, Romo L, et al. Family  Holst B, Schwartz TW. Constitutive ghrelin receptor activity as trios analysis of common polymorphisms in the obestatin/ghrelin, BDNF a signaling set-point in appetite regulation. Trends Pharmacol Sci and AGRP genes in patients with anorexia nervosa: association with 2004;25:113–7. subtype, body-mass index, severity and age of onset. Psychoneur-  Holst B, Lang M, Brandt E, Bach A, Howard A, Frimurer TM, et al. Ghrelin oendocrinology 2007;32:106–13. receptor inverse agonists: identiﬁcation of an active peptide core and its Ying BW, Song XB, Fan H, Wang LL, Li YS, Cheng Z, et al. Plasma ghrelin interaction epitopes on the receptor. Mol Pharmacol 2006;70:936–46. levels and weight loss in Chinese Uygur patients with chronic obstructive  Wang HJ, Geller F, Dempﬂe A, Schauble N, Friedel S, Lichtner P, et al. pulmonary disease. J Int Med Res 2008;36:1371–7. Ghrelin receptor gene: identiﬁcation of several sequence variants in Otto B, Cuntz U, Fruehauf E, Wawarta R, Folwaczny C, Riepl RL, et al. extremely obese children and adolescents, healthy normal-weight and Weight gain decreases elevated plasma ghrelin concentrations of patients underweight students, and children with short normal stature. J Clin with anorexia nervosa. Eur J Endocrinol 2001;145:669–73. Endocrinol Metab 2004;89:157–62. Neary NM, Small CJ, Wren AM, Lee JL, Druce MR, Palmieri C, et al. Ghrelin  Pantel J, Legendre M, Cabrol S, Hilal L, Hajaji Y, Morisset S, et al. Loss of increases energy intake in cancer patients with impaired appetite: acute, constitutive activity of the growth hormone secretagogue receptor in randomized, placebo-controlled trial. J Clin Endocrinol Metab familial short stature. J Clin Invest 2006;116:760–8. 2004;89:2832–6.  Kobelt P, Helmling S, Stengel A, Wlotzka B, Andresen V, Klapp BF, et al. Wynne K, Giannitsopoulou K, Small CJ, Patterson M, Frost G, Ghatei MA, Anti-ghrelin Spiegelmer NOX-B11 inhibits neurostimulatory and orexi- et al. Subcutaneous ghrelin enhances acute food intake in malnourished genic effects of peripheral ghrelin in rats. Gut 2006;55:788–92. patients who receive maintenance peritoneal dialysis: a randomized,  Shearman LP, Wang SP, Helmling S, Stribling DS, Mazur P, Ge L, et al. placebo-controlled trial. J Am Soc Nephrol 2005;16:2111–8. Ghrelin neutralization by a ribonucleic acid–SPM ameliorates obesity in Ashby DR, Ford HE, Wynne KJ, Wren AM, Murphy KG, Busbridge M, et al. diet-induced obese mice. Endocrinology 2006;147:1517–26. Sustained appetite improvement in malnourished dialysis patients by  Helmling S, Maasch C, Eulberg D, Buchner K, Schroder W, Lange C, et al. daily ghrelin treatment. Kidney Int 2009;76:199–206. Inhibition of ghrelin action in vitro and in vivo by an RNA-Spiegelmer. Nagaya N, Kojima M, Kangawa K. Ghrelin, a novel growth hormone- Proc Natl Acad Sci U S A 2004;101:13174–9. releasing peptide, in the treatment of cardiopulmonary-associated  Becskei C, Bilik KU, Klussmann S, Jarosch F, Lutz TA, Riediger T. The anti- cachexia. Intern Med 2006;45:127–34. ghrelin Spiegelmer NOX-B11-3 blocks ghrelin- but not fasting-induced Nagaya N, Moriya J, Yasumura Y, Uematsu M, Ono F, Shimizu W, et al. neuronal activation in the hypothalamic arcuate nucleus. J Neuro- Effects of ghrelin administration on left ventricular function, exercise endocrinol 2008;20:85–92. capacity, and muscle wasting in patients with chronic heart failure.  Zorrilla EP, Iwasaki S, Moss JA, Chang J, Otsuji J, Inoue K, et al. Vaccination Circulation 2004;110:3674–9. against weight gain. Proc Natl Acad Sci U S A 2006;103:13226–31. Nagaya N, Itoh T, Murakami S, Oya H, Uematsu M, Miyatake K, Kangawa K.  Lu SC, Xu J, Chinookoswong N, Liu S, Steavenson S, Gegg C, et al. An Treatment of cachexia with ghrelin in patients with COPD. Chest acyl-ghrelin-speciﬁc neutralizing antibody inhibits the acute ghrelin- 2005;128:1187–93. mediated orexigenic effects in mice. Mol Pharmacol 2009;75:901–7. Strassburg S, Anker SD, Castaneda TR, Burget L, Perez-Tilve D, Pﬂuger PT,  Mayorov AV, Amara N, Chang JY, Moss JA, Hixon MS, Ruiz DI, et al. et al. Long-term effects of ghrelin and ghrelin receptor agonists Catalytic antibody degradation of ghrelin increases whole-body metabolic on energy balance in rats. Am J Physiol Endocrinol Metab 2008;295: rate and reduces refeeding in fasting mice. Proc Natl Acad Sci U S A E78–84. 2008;105:17487–92.