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Ghrelin and anorexia nervosa: A psychosomatic perspective
Nutrition 27 (2011) 988–993
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Review
Ghrelin and anorexia nervosa: A psychosomatic perspective Kazuma Ogiso M.D., Akihiro Asakawa M.D., Ph.D., Haruka Amitani M.D., Akio Inui M.D., Ph.D. * Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka, Kagoshima, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 23 November 2009 Accepted 2 May 2011
Anorexia nervosa (AN) is a serious medical illness associated with gastrointestinal, metabolic, and psychological complications, and there are no effective pharmacologic treatments for the condition. Recent studies have suggested that the regulatory peptides, including ghrelin, are involved in the pathologic feeding behavior of AN. Previous studies have indicated that plasma total ghrelin and acyl ghrelin levels in patients with AN are higher than in controls, and the ratio of des-acyl ghrelin to acyl ghrelin in AN tend to be higher than in controls. In addition, ghrelin has been reported to stimulate appetite and food intake in various diseases, including chronic heart failure, chronic obstructive pulmonary disease, and cancer. Because it is speculated that difficulties in resolving the underlying psychological condition preclude reversal of the pathologic feeding behavior in AN, ghrelin is expected to be applied in a clinical setting as a new treatment. In this review, we describe the role of ghrelin in the pathophysiology and potential treatment of AN along the gut–brain axis. Ó 2011 Elsevier Inc. All rights reserved.
Keywords: Anorexia Bulimia Ghrelin
Introduction Anorexia nervosa (AN) is characterized by extremely low body weight and a fear of its increase. Common symptoms in patients with AN include restrictive behavior, binge eating, purgative behavior, excessive exercise, repeated body checking, and body image disturbance. They often complain of physical symptoms such as abdominal discomfort and constipation. Patients with AN have also been characterized by perfectionism, obsessive–compulsiveness, neuroticism, negative emotions, low self-efficacy, and low cooperativeness, and many are diagnosed with anxiety and depressive disorder and obsessive–compulsive disorder [1]. Although these comorbidities in patients with AN are thought to contribute to persistent food restriction and body image disturbance, its etiology is poorly understood. Recently, some studies have focused on a biological approach to investigate the systems of hunger regulation, motivation, reward, and energy metabolism regulation in patients with AN. Regarding hunger regulation in particular, gut–brain peptides have been thought to be involved in the pathogenesis of AN based on numerous data showing that alterations of central and/or peripheral peptidergic signaling are accompanied by disturbed regulation of feeding and body weight, including anorexigenic
* Corresponding author. Tel.: þ81-99-275-5748; fax: þ81-99-275-5749. E-mail address: [email protected] (A. Inui). 0899-9007/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.nut.2011.05.005
corticotropin-releasing factor and melanocortin and orexigenic neuropeptide Y (NPY) and ghrelin [2]. Ghrelin is one of the important brain–gut peptides and an endogenous ligand of the growth hormone secretagogue (GHS) receptor discovered in the stomach and the first orexigenic peptide of the periphery [3,4]. A 28-amino-acid peptide cleaved from the 117-amino acid precursor preproghrelin, ghrelin is a member of the motilin–ghrelin family of gastrointestinal (GI) hormones because of the structural and functional resemblance between the two peptides, including prokinetic GI motor activities. Because plasma ghrelin levels can be measured, much attention has been paid to the relation of this peptide to the feeding behavior of humans and to the implication in AN and other cachectic disorders.
Ghrelin, appetite, and GI motility Ghrelin undergoes octanoylation at Ser3, which is essential for its binding to the ghrelin receptor (GHS-R1a), the only known receptor transducing a ghrelin signal, and is expressed in many central and peripheral tissues, such as the hypothalamus, pituitary gland, pancreas, and placenta. Des-acyl ghrelin, the nonacylated form, circulates at much higher levels than ghrelin and is the major form isolated from the stomach. Obestatin, a 23-amino-acid peptide derived from preproghrelin, is the
K. Ogiso et al. / Nutrition 27 (2011) 988–993
newest member of the family for which opposing actions to ghrelin on feeding and GI motility have been reported [5]. Plasma ghrelin levels increase before a meal and decrease shortly afterward in association with changes in appetite [4,5]. Ghrelin potently stimulates feeding in many species, including humans, after peripheral administration and decreases energy expenditure as measured by metabolic rate, body temperature, locomotion, and sympathetic nervous activity. By acting on vagal afferents or centrally, ghrelin activates neurons in the hypothalamic arcuate nucleus that co-secrete the orexigenic peptides NPY and agouti-related peptide. Arcuate neurons project to the paraventricular, lateral hypothalamic, and other nuclei, and orexin in the lateral hypothalamus mediates some of the orexigenic activity of ghrelin. Ghrelin not only regulates hunger by stimulating the hypothalamus area of the brain but also affects the part of the brain responsible for pleasure and reward systems, opening new avenues for investigation. Hedonic feeding behavior can be described as non-homeostatic in that it occurs in the absence of nutritional and caloric deficiency [6]. Using functional magnetic resonance imaging (fMRI), ghrelin has been shown to increase the neural response to food pictures in regions of the brain implicated in reward processing, such as the amygdala, orbitofrontal cortex, anterior insula, and striatum in healthy volunteers [7]. The sensation of hunger is significantly increased after ghrelin and correlates positively with increases in blood flow of the regions. The striatum and ventral tegmental area (VTA), two dopaminergic regions, are also modulated by ghrelin, which is in agreement with previous rodent studies in which injections of ghrelin locally or peripherally stimulated dopamine neuronal activity in the VTA and feeding behavior [8]. Ghrelin increases anxiety/ alertness, stimulates long-term potentiation, and hippocampal spine synapse formation, enhances spatial learning and memory, and restores memory deficit in ghrelin knockout mice [9,10]. These results indicate that ghrelin may have an integrative role in the behavioral response to starvation, an adaptive advantage to animals and humans during evolution. Ghrelin stimulates fasted motor activity irrespective of the presence of food in the stomach by activating NPY neurons in the brain through receptors on vagal afferents, which is consistent with the presence for GHS-R1a and modulatory effects of acyl ghrelin on gastric vagal afferents [4]. The gastro-prokinetic effect of ghrelin underlies the orexigenic effect of the peptide. Vagally mediated and independent GI motor effects have been reported for ghrelin, similar to motilin. Ghrelin may activate receptors in the enteric nervous system, and recent studies have provided evidence for the presence of GHS-R1a in the intestinal wall and myenteric neurons. In vitro, ghrelin enhances contractions induced by electrical field stimulation in stomach preparations and evokes cholinergically mediated contractions in jejunum preparations. Thus, local and central pathways exist for the enterokinetic effect of ghrelin, but only central pathways appear to be operational in normal situations, reinforcing the importance of the gut–brain axis in modulating GI function and behavior [4,5]. The concept that des-acyl ghrelin is a non-functional peptide has been challenged, and various effects including anorexigenic and anti-prokinetic activities of the peptide have been shown [10]. Des-acyl ghrelin disrupts fasted motor activity in the stomach, through hormonal mechanisms with an involvement of the corticotropin-releasing factor type 2 receptor, in accordance with the anorexigenic property of the peptide. Obestatin was discovered as a physiologic opponent of ghrelin, and the amide structure of obestatin at its carboxyl terminal appeared to be important. Obestatin is rapidly degraded in the blood and does
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not cross the blood–brain barrier, in contrast to acyl- and desacyl ghrelin, which cross the blood–brain barrier in the brainto-blood and blood-to-brain directions [11]. However, obestatin can affect feeding and fasted motor activity in an inhibitory manner through hormonal and vagal mechanisms with an involvement of corticotropin-releasing factor functions [5,10]. Ghrelin and AN Patients with AN often cannot increase food intake, not only out of fear of obesity but also because of chronic or recurrent upper abdominal discomfort and fullness and chronic constipation. Abdominal discomfort is associated with chronic malnutrition, which induces functional and organic changes in the gastrointestinal tracts [12,13]. Because ghrelin is associated with increasing hunger sensations, food intake, and gut motility, the possible role of ghrelin in the pathogenesis of AN has been extensively investigated. In several studies, plasma total ghrelin levels were measured in patients with AN (Table 1) [14–28]. Although most studies have found that plasma total ghrelin levels are higher than in healthy controls, it remains unknown why ghrelin levels increase in patients with AN. Janas-Kozik et al. [14] implied that plasma ghrelin levels are associated with the pathologic feeding behavior in patients with AN restricting type (AN-R). Tanaka et al. [15] suggested that habitual binge/purge behavior influences plasma ghrelin levels because plasma ghrelin levels in patients with bulimia nervosa (BN) purging type were similar to those in patients with AN-R and AN binge-eating/purging type despite differences in nutritional parameters and were higher than in patients with BN non-purging type and controls despite similar nutritional parameters. In contrast, Troisi et al. [16] suggested that plasma ghrelin levels reflect nutritional status rather than specific patterns of disordered eating behavior. These results indicate that the relation between ghrelin and eating behavior is complicated. Interestingly, the ghrelin receptor is expressed in the central nervous system such as in the VTA, accumbens, hippocampus, and orbitofrontal cortex (OFC) relating to the reward system, and amygdala relating to anxiety. Indeed, microinjection of ghrelin into the VTA has elicited a strong feeding behavior [29]. Because ghrelin has been reported to be associated with reward systems and increasing anxiety, it may directly affect disordered eating behavior through its receptors in these areas of the central nervous system through the blood–brain barrier. There have been many studies of the association between AN and ghrelin, but in those studies the measured variables were total ghrelin, which included acyl ghrelin and des-acyl ghrelin. Acyl ghrelin and des-acyl ghrelin are thought to have opposite effects; that is, acyl ghrelin stimulates food intake and gut motility [5], and des-acyl ghrelin has been shown to significantly decrease food intake in food-deprived mice and decrease gastric emptying [30]. In some studies, des-acyl ghrelin has been reported to oppose acyl ghrelin-induced hyperphagic effects [31] and to block the stimulatory effects on food intake induced by acyl ghrelin [32]. These results indicate that acyl ghrelin and des-acyl ghrelin interact with each other. Considering the association between acyl ghrelin and des-acyl ghrelin, it is very important to measure these forms separately. However, a few reports have referred to the association between ghrelin forms and AN (Table 2) [33–37]. Hotta et al. [33] showed that plasma des-acyl ghrelin levels are significantly higher in patients with AN than in controls, and plasma acyl ghrelin levels tend to be slightly higher in patients with AN than in controls without a significant difference. Other
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Table 1 Plasma total ghrelin levels in patients with AN References
Subtype of ED
n
Total ghrelin level
Method of measurement
Janas-Kozik et al., 2007 [14] Tanaka et al., 2003 [20]
AN-R AN-R AN-BP AN-R AN-BP AN-R AN-BP AN AN AN AN-R AN-BP AN AN AN AN-R AN-BP AN AN ED AN-R AN-BP BN-P
30 19 20 14 13 21 19 5 20 8 13 2 19 22 6 19 20 9 36 11 3 6 2
AN-R > control AN-BP > AN-R >control
RIA RIA
AN-R > control AN-BP > control AN-R > control AN-BP > control AN > control AN > control AN > control AN > control
RIA
RIA ELISA RIA RIA
AN > control AN > control AN > control AN-BP > AN-R >control
RIA RIA RIA RIA
AN > control AN > control ED > control
RIA RIA RIA
Tanaka et al., 2004 [21] Tanaka et al., 2003 [15] et al., 2003 [22] Nedvıdkova Monteleone et al., 2008 [18] Sedlackova et al., 2010 [19] Troisi et al., 2005 [16] Misra et al., 2004 [23] Misra et al., 2005 [24] Rigamonti et al., 2002 [25] Tanaka et al., 2003 [26] Tolle et al., 2003 [27] Otto et al., 2001 [28] Uehara et al., 2005 [17]
RIA
AN, anorexia nervosa; AN-BP, anorexia nervosa binge-eating/purging type; AN-R, anorexia nervosa restricting type; BN-P, bulimia nervosa purging type; ED, eating disorder; ELISA, enzyme-linked immunosorbent assay; RIA, radioimmunoassay
studies have demonstrated similar results [34–36]. Koyama et al. [34] suggested that plasma des-acyl ghrelin levels in patients with AN-R start decreasing very rapidly after body weight has been regained through treatment, suggesting that des-acyl ghrelin is altered in a manner that depends on nutritional status. Considering the roles of acyl ghrelin and des-acyl ghrelin, not only are the absolute levels but also the ratio of these forms are very important (Table 2). Hotta et al. [33] showed that the ratio of des-acyl ghrelin to acyl ghrelin is higher in patients with AN than in controls. Nakahara et al. [36] also demonstrated a high ratio of acyl ghrelin to des-acyl ghrelin in patients with AN. In other studies, the ratio of des-acyl ghrelin to acyl ghrelin in patients with AN-R has tended to be higher than in controls when estimating their results (statistical differences were not known) [33, 35,37]. However, the ratio of acyl ghrelin to total ghrelin has not significantly different between patients with AN and controls [17, 34]. These results imply that increased des-acyl ghrelin levels might prevent patients with AN from eating and thus gaining body weight. Recently, ghrelin O-acyltransferase (GOAT) was identified as the endogenous key enzyme responsible for ghrelin acylation. Müller et al. [38] showed that the G/G genotype at single nucleotide polymorphism (SNP) rs10096097 might be associated
with AN and that homozygous risk G-allele carriers may have an increased risk for AN. Although the potential implication of SNPs for AN remains unknown, loss-of-function mutations in GOAT might disturb the ratio of acyl ghrelin to des-acyl ghrelin and might lead to impaired eating behavior. Obestatin has also been reported to increase in patients with AN. Harada et al. [35] showed that plasma obestatin levels in AN-R are higher than in controls. Nakahara et al. [36] also demonstrated that plasma obestatin levels are higher in patients with AN and lower in obese patients than in controls. They suggested that obestatin is a nutritional marker reflecting body adiposity and insulin resistance. However, plasma obestatin levels in patients with AN were higher than in constitutionally thin women who were matched for body mass index and in whom obestatin levels were similar to those in control groups without significant differences [39]. Monteleone et al. [18] indicated that plasma obestatin levels are increased in patients with AN but not in those with BN compared with control groups. Sedlackova et al. [19] also demonstrated that fasting plasma obestatin levels are increased in patients with AN and with BN but are higher in patients with AN than in those with BN. They suggested that different fasting obestatin levels in AN and BN could demonstrate their diverse functions in appetite and eating
Table 2 Plasma acyl/des-acyl ghrelin levels and ratio in patients with AN References
Subtype of ED
n
Acyl ghrelin
Des-acyl ghrelin
Des-acyl/acyl ghrelin ratio
Method of measurement
Hotta et al., 2004 [33]
AN
30
Koyama et al., 2010 [34] Harada et al., 2008 [35] Nakahara et al., 2008 [36] Ogiso et al., 2011 [37]
AN-R AN-R AN AN-R
5 10 11 7
AN > controly AN > control AN-R > controly AN-R > controly AN > controly AN-R > control
AN > control d AN-R > control AN-R > control AN > control AN-R > control
6.14 (AN) > 3.34 (control) d 14.5 (AN-R) > 11.5 (control)* 11.9 (AN-R) > 10.3 (control)* 12.7 (AN) > 10.1 (control) 4.8 (AN-R) > 3.9 (control)*
ELISA RIA ELISA ELISA ELISA ELISA
AN, anorexia nervosa; AN-R, anorexia nervosa restricting type; ED, eating disorder; ELISA, enzyme-linked immunosorbent assay; RIA, radioimmunoassay * The des-acyl/acyl ghrelin ratio was estimated by dividing the mean acyl ghrelin level by the mean des-acyl ghrelin level, and significant differences were unknown because there were not shown in the original reports. y Plasma acyl ghrelin levels in the AN or AN-R group tended to be higher than in the control group in each study, but there were no significant differences between the AN or AN-R group and the control group (P > 0.05).
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suppression. In addition, Germain et al. [40] recently demonstrated that total and acylated ghrelin and obestatin circadian levels are increased in patients with AN-R compared with controls but decreased in patients with AN binge-eating/purging type and those with BN. The assessment of these peptides may help in revealing the differences in eating behavior between ANR and AN binge-eating/purging type. Further research is needed because there are few reports of an association between AN and obestatin compared with ghrelin. Collectively in these results, plasma total ghrelin and acyl ghrelin levels in patients with AN were higher than in controls, and the ratio of des-acyl ghrelin to acyl ghrelin in AN tended to be higher than in controls. Des-acyl ghrelin has been found to disrupt fasted motility in the antrum [10] and oppose acyl ghrelin-induced hyperphagic effects [31,32]. These findings suggest that the tendency of increasing plasma des-acyl ghrelin levels in patients with AN may contribute to the etiology of AN through the interaction between acyl ghrelin and des-acyl ghrelin. It is very important to measure acyl ghrelin and des-acyl ghrelin separately in patients with AN for further investigations.
Clinical application of ghrelin Intravenous infusion of ghrelin has been reported to increase food intake and body weight in healthy subjects [41] and to stimulate appetite and food intake in patients with chronic heart failure, chronic obstructive pulmonary disease, and cancer [42–44]. With respect to the effects of acyl ghrelin, such as stimulating food intake and gut motility, ghrelin is expected to be effective in AN because chronic malnutrition induces functional and organic changes in the GI tract [12,13]. Hotta et al. [45] demonstrated that the intravenous administration of ghrelin in patients with AN-R twice a day for 14 d improves epigastric discomfort or constipation and increases the hunger score, which is related to gastric emptying. Although the increases of body weight in patients with AN was 1.5 to 2.4 kg, daily energy intake during ghrelin infusion increased by 12% to 36% compared with the pretreatment period. These results imply that ghrelin has the potential as a new treatment for AN. In Japan, a phase 3 clinical study with intravenous ghrelin in patients with AN is underway, which could address whether and how normalization of the feeding–regulatory circuitry corrects metabolic, GI, and behavioral abnormalities of these patients. In contrast, although Miljic et al. [46] reported that singledose continuous administration of ghrelin in patients with AN for 5 h failed to affect appetite, further investigations are needed such as long-term and repeated administration because this study was designed to administer ghrelin in a single dose. Anorexia nervosa is considered a complex multifactorial disease, including the diversity of psychosocial problems. Ghrelin will be effective in patients with AN complaining of symptoms such as upper abdominal discomfort because ghrelin increases gut motility. Therefore, it may be important to select the patients with AN with decreased gut motility and complaints of abdominal discomfort in clinical studies. Moreover, long-term administration would be needed to evaluate the effect of ghrelin on gaining body weight because a 1-kg weight gain requires 7000 to 8000 kcal. If the clinical trials were designed to administer ghrelin for a long-term period to patients with AN complaining of abdominal discomfort, the effect of ghrelin in patients with AN would become increasingly apparent. Further studies are required to clarify the therapeutic potential of ghrelin in patients with AN.
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More recently, Barnett et al. [47] demonstrated that the administration of a GOAT inhibitor improves glucose tolerance and decreases weight gain in wild-type mice but not in ghrelindeficient mice. These results indicate that a GOAT inhibitor might be expected to help pave the way for clinical targeting of GOAT in metabolic diseases such as obesity and diabetes mellitus. Conversely, a GOAT activator, which has not been reported yet, may be a potential new treatment of AN if it improves food intake and body weight gain in patients with AN. A psychosomatic perspective Brain–gut peptides may be important not only in the regulation of feeding and metabolism but also in other neuroendocrine and behavior functions. Previously, some studies have demonstrated an association between brain–gut peptides and feeding behavior using fMRI and SNPs. For instance, using fMRI, peptide YY, a physiological gut-derived satiety signal, has been found to modulate the activity of the OFC and other corticolimbic and higher cortical regions, independently of meal-related sensory experiences. Peptide YY modulation of cortical and hypothalamic brain areas predicts feeding behavior in humans. As a result, rewarding aspects of food are decreased by peptide YY modulation of OFC [48]. Similarly, using fMRI, leptin replacement in genetically leptin-deficient adults has been found to decrease brain activation in regions linked to hunger (insula and parietal and temporal cortices) and simultaneously increase activation in regions linked to inhibition and satiety (prefrontal cortex) during viewing of food-related stimuli [49]. Ghrelin administrated intravenously to healthy volunteers during fMRI has been found to increase the neural response to food pictures in regions of the brain, including the amygdala, OFC, anterior insula, and striatum, implicated in encoding the incentive value of food cues. The effects of ghrelin on the amygdala and OFC response have been correlated with self-rated hunger ratings. This demonstrates that metabolic signals such as ghrelin may favor food consumption by increasing the hedonic and incentive responses to food-related cues [7]. The SNPs of brain–gut peptides have been thought to affect feeding behavior. The mutation of melanocortin-4 receptor, which is related to anorexigenic signals, has led to hyperphagia, hyperinsulinemia, and increased lean body mass [50]. NPY is important not only in stimulating food intake but also in anxiolytic peptides, which are released by stress. A SNP located in the promoter region alters NPY expression, suggesting that genetic variation in human NPY expression affects stress response and emotion [51]. These investigations using fMRI and SNPs support the idea that brain–gut peptides may play a role in feeding behaviors in humans. Indeed, several SNPs of the ghrelin gene have been found, which is associated with AN bingeing/purging subtype or BN, supporting the hypothesis that ghrelin polymorphism may increase susceptibility to binge eating [52,53]. Recently, the autoantibodies against feeding–regulatory peptides such as a-melanocyte–stimulating hormone in patients with AN and BN have been reported, with serum levels being correlated with psychopathologic traits in these patients [54]. In patients with AN, the levels of immunoglobulin G of autoantibodies reactive with acyl ghrelin decreased. Immunoglobulin G autoantibodies exist mainly as an immune complex with desacyl ghrelin accompanied by a decrease of a free fraction of these autoantibodies binding acyl and des-acyl ghrelin levels. This decrease of bioavailable ghrelin autoantibodies may underlie a long-term increase of plasma ghrelin levels and the resulting phenomenon of ghrelin resistance in malnourished patients
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with AN [55]. The autoantibodies could alter the feeding– regulatory circuitry and behavior by changing the signaling of the molecule ranging from transport to neutralization. The “mixed” signal about satiety and desire to feed could contribute to the ambivalence about food, the dissociation that anorexics often display between decreased caloric intake and obsessive thoughts about food [1,2]. This mixed signal could underlie bulimic binging behavior in which a relative decrease in anorexigenic signaling is characteristic, as is an obsessional preoccupation with body weight and body shape, an aversively conditioned learning. Ghrelin secretion in AN is amplified in its cephalic phase as in other GI hormones and may aim to counteract the patients’ rigid control over their food intake, eventually facilitating binge-eating behavior [56]. Additional investigations of the relations between brain–gut peptides and feeding behavior using new techniques, such as fMRI, SNPs, and autoantibodies, would help elaborate on the psychopathology. Conclusion Acyl ghrelin, des-acyl ghrelin, and obestatin derived from alternative splicing or extensive post-translational modifications of preproghrelin may be part of a system with multiple effector elements and form the basis of an integrated gut–brain axis modulating appetite and behavior. Ghrelin peptides may have a role in feeding behavior, adaptation to starvation, reward mechanisms, emotional behavior, and stress responses in animals and humans. Neuroimaging studies have suggested ventral and dorsal neural circuit dysfunctions in patients with eating disorders, with altered metabolisms of serotonin and dopamine that are closely associated to ghrelin, contributing to their puzzling symptoms [57]. More sophisticated analyses are needed to assess the central nervous system activity of ghrelin signaling in humans and to identify the specific pathways that may underlie the pathologic behaviors in patients with AN. However, the investigation of the ghrelin peptide system will open up a new opportunity for tackling psychosomatic disorders beyond the GI tract, particularly anorexia/cachexia syndrome and obesity/metabolic syndrome, two disorders at the extreme of the body weight continuum. References [1] Kaye WH, Bulik CM, Thornton L, Barbarich N, Masters K. Comorbidity of anxiety disorders with anorexia and bulimia nervosa. Am J Psychiatry 2004;161:2215–21. [2] Inui A. Eating behavior in anorexia nervosadan excess of both orexigenic and anorexigenic signaling? Mol Psychiatry 2001;6:620–4. [3] Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone–releasing acylated peptide from stomach. Nature 1999;402:656–60. [4] Inui A. Ghrelin: An orexigenic and somatotrophic signal from the stomach. Nat Rev Neurosci 2001;2:551–60. [5] Chen CY, Asakawa A, Fujimiya M, Lee SD, Inui A. Ghrelin gene products and the regulation of food intake and gut motility. Pharmacol Rev 2009;61:430–81. [6] Depoortere I. Targeting the ghrelin receptor to regulate food intake. Regul Pept 2009;156:13–23. [7] Malik S, McGlone F, Bedrossian D, Dagher A. Ghrelin modulates brain activity in areas that control appetitive behavior. Cell Metab 2008;7:400–9. [8] Abizaid A, Liu ZW, Andrews ZB, Shanabrough M, Borok E, Elsworth JD, et al. Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite. J Clin Invest 2006;116:3229–39. [9] Diano S, Farr SA, Benoit SC, McNay EC, da Silva I, Horvath B, et al. Ghrelin controls hippocampal spine synapse density and memory performance. Nat Neurosci 2006;9:381–8. [10] Chen CY, Inui A, Asakawa A, Fujino K, Kato I, Chen CC, et al. Des-acly ghrelin acts by CRF type 2 receptors to disrupt fasted stomach motility in conscious rats. Gastroenterology 2005;129:8–25.
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Review
Ghrelin and anorexia nervosa: A psychosomatic perspective Kazuma Ogiso M.D., Akihiro Asakawa M.D., Ph.D., Haruka Amitani M.D., Akio Inui M.D., Ph.D. * Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka, Kagoshima, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 23 November 2009 Accepted 2 May 2011
Anorexia nervosa (AN) is a serious medical illness associated with gastrointestinal, metabolic, and psychological complications, and there are no effective pharmacologic treatments for the condition. Recent studies have suggested that the regulatory peptides, including ghrelin, are involved in the pathologic feeding behavior of AN. Previous studies have indicated that plasma total ghrelin and acyl ghrelin levels in patients with AN are higher than in controls, and the ratio of des-acyl ghrelin to acyl ghrelin in AN tend to be higher than in controls. In addition, ghrelin has been reported to stimulate appetite and food intake in various diseases, including chronic heart failure, chronic obstructive pulmonary disease, and cancer. Because it is speculated that difficulties in resolving the underlying psychological condition preclude reversal of the pathologic feeding behavior in AN, ghrelin is expected to be applied in a clinical setting as a new treatment. In this review, we describe the role of ghrelin in the pathophysiology and potential treatment of AN along the gut–brain axis. Ó 2011 Elsevier Inc. All rights reserved.
Keywords: Anorexia Bulimia Ghrelin
Introduction Anorexia nervosa (AN) is characterized by extremely low body weight and a fear of its increase. Common symptoms in patients with AN include restrictive behavior, binge eating, purgative behavior, excessive exercise, repeated body checking, and body image disturbance. They often complain of physical symptoms such as abdominal discomfort and constipation. Patients with AN have also been characterized by perfectionism, obsessive–compulsiveness, neuroticism, negative emotions, low self-efficacy, and low cooperativeness, and many are diagnosed with anxiety and depressive disorder and obsessive–compulsive disorder [1]. Although these comorbidities in patients with AN are thought to contribute to persistent food restriction and body image disturbance, its etiology is poorly understood. Recently, some studies have focused on a biological approach to investigate the systems of hunger regulation, motivation, reward, and energy metabolism regulation in patients with AN. Regarding hunger regulation in particular, gut–brain peptides have been thought to be involved in the pathogenesis of AN based on numerous data showing that alterations of central and/or peripheral peptidergic signaling are accompanied by disturbed regulation of feeding and body weight, including anorexigenic
* Corresponding author. Tel.: þ81-99-275-5748; fax: þ81-99-275-5749. E-mail address: [email protected] (A. Inui). 0899-9007/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.nut.2011.05.005
corticotropin-releasing factor and melanocortin and orexigenic neuropeptide Y (NPY) and ghrelin [2]. Ghrelin is one of the important brain–gut peptides and an endogenous ligand of the growth hormone secretagogue (GHS) receptor discovered in the stomach and the first orexigenic peptide of the periphery [3,4]. A 28-amino-acid peptide cleaved from the 117-amino acid precursor preproghrelin, ghrelin is a member of the motilin–ghrelin family of gastrointestinal (GI) hormones because of the structural and functional resemblance between the two peptides, including prokinetic GI motor activities. Because plasma ghrelin levels can be measured, much attention has been paid to the relation of this peptide to the feeding behavior of humans and to the implication in AN and other cachectic disorders.
Ghrelin, appetite, and GI motility Ghrelin undergoes octanoylation at Ser3, which is essential for its binding to the ghrelin receptor (GHS-R1a), the only known receptor transducing a ghrelin signal, and is expressed in many central and peripheral tissues, such as the hypothalamus, pituitary gland, pancreas, and placenta. Des-acyl ghrelin, the nonacylated form, circulates at much higher levels than ghrelin and is the major form isolated from the stomach. Obestatin, a 23-amino-acid peptide derived from preproghrelin, is the
K. Ogiso et al. / Nutrition 27 (2011) 988–993
newest member of the family for which opposing actions to ghrelin on feeding and GI motility have been reported [5]. Plasma ghrelin levels increase before a meal and decrease shortly afterward in association with changes in appetite [4,5]. Ghrelin potently stimulates feeding in many species, including humans, after peripheral administration and decreases energy expenditure as measured by metabolic rate, body temperature, locomotion, and sympathetic nervous activity. By acting on vagal afferents or centrally, ghrelin activates neurons in the hypothalamic arcuate nucleus that co-secrete the orexigenic peptides NPY and agouti-related peptide. Arcuate neurons project to the paraventricular, lateral hypothalamic, and other nuclei, and orexin in the lateral hypothalamus mediates some of the orexigenic activity of ghrelin. Ghrelin not only regulates hunger by stimulating the hypothalamus area of the brain but also affects the part of the brain responsible for pleasure and reward systems, opening new avenues for investigation. Hedonic feeding behavior can be described as non-homeostatic in that it occurs in the absence of nutritional and caloric deficiency [6]. Using functional magnetic resonance imaging (fMRI), ghrelin has been shown to increase the neural response to food pictures in regions of the brain implicated in reward processing, such as the amygdala, orbitofrontal cortex, anterior insula, and striatum in healthy volunteers [7]. The sensation of hunger is significantly increased after ghrelin and correlates positively with increases in blood flow of the regions. The striatum and ventral tegmental area (VTA), two dopaminergic regions, are also modulated by ghrelin, which is in agreement with previous rodent studies in which injections of ghrelin locally or peripherally stimulated dopamine neuronal activity in the VTA and feeding behavior [8]. Ghrelin increases anxiety/ alertness, stimulates long-term potentiation, and hippocampal spine synapse formation, enhances spatial learning and memory, and restores memory deficit in ghrelin knockout mice [9,10]. These results indicate that ghrelin may have an integrative role in the behavioral response to starvation, an adaptive advantage to animals and humans during evolution. Ghrelin stimulates fasted motor activity irrespective of the presence of food in the stomach by activating NPY neurons in the brain through receptors on vagal afferents, which is consistent with the presence for GHS-R1a and modulatory effects of acyl ghrelin on gastric vagal afferents [4]. The gastro-prokinetic effect of ghrelin underlies the orexigenic effect of the peptide. Vagally mediated and independent GI motor effects have been reported for ghrelin, similar to motilin. Ghrelin may activate receptors in the enteric nervous system, and recent studies have provided evidence for the presence of GHS-R1a in the intestinal wall and myenteric neurons. In vitro, ghrelin enhances contractions induced by electrical field stimulation in stomach preparations and evokes cholinergically mediated contractions in jejunum preparations. Thus, local and central pathways exist for the enterokinetic effect of ghrelin, but only central pathways appear to be operational in normal situations, reinforcing the importance of the gut–brain axis in modulating GI function and behavior [4,5]. The concept that des-acyl ghrelin is a non-functional peptide has been challenged, and various effects including anorexigenic and anti-prokinetic activities of the peptide have been shown [10]. Des-acyl ghrelin disrupts fasted motor activity in the stomach, through hormonal mechanisms with an involvement of the corticotropin-releasing factor type 2 receptor, in accordance with the anorexigenic property of the peptide. Obestatin was discovered as a physiologic opponent of ghrelin, and the amide structure of obestatin at its carboxyl terminal appeared to be important. Obestatin is rapidly degraded in the blood and does
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not cross the blood–brain barrier, in contrast to acyl- and desacyl ghrelin, which cross the blood–brain barrier in the brainto-blood and blood-to-brain directions [11]. However, obestatin can affect feeding and fasted motor activity in an inhibitory manner through hormonal and vagal mechanisms with an involvement of corticotropin-releasing factor functions [5,10]. Ghrelin and AN Patients with AN often cannot increase food intake, not only out of fear of obesity but also because of chronic or recurrent upper abdominal discomfort and fullness and chronic constipation. Abdominal discomfort is associated with chronic malnutrition, which induces functional and organic changes in the gastrointestinal tracts [12,13]. Because ghrelin is associated with increasing hunger sensations, food intake, and gut motility, the possible role of ghrelin in the pathogenesis of AN has been extensively investigated. In several studies, plasma total ghrelin levels were measured in patients with AN (Table 1) [14–28]. Although most studies have found that plasma total ghrelin levels are higher than in healthy controls, it remains unknown why ghrelin levels increase in patients with AN. Janas-Kozik et al. [14] implied that plasma ghrelin levels are associated with the pathologic feeding behavior in patients with AN restricting type (AN-R). Tanaka et al. [15] suggested that habitual binge/purge behavior influences plasma ghrelin levels because plasma ghrelin levels in patients with bulimia nervosa (BN) purging type were similar to those in patients with AN-R and AN binge-eating/purging type despite differences in nutritional parameters and were higher than in patients with BN non-purging type and controls despite similar nutritional parameters. In contrast, Troisi et al. [16] suggested that plasma ghrelin levels reflect nutritional status rather than specific patterns of disordered eating behavior. These results indicate that the relation between ghrelin and eating behavior is complicated. Interestingly, the ghrelin receptor is expressed in the central nervous system such as in the VTA, accumbens, hippocampus, and orbitofrontal cortex (OFC) relating to the reward system, and amygdala relating to anxiety. Indeed, microinjection of ghrelin into the VTA has elicited a strong feeding behavior [29]. Because ghrelin has been reported to be associated with reward systems and increasing anxiety, it may directly affect disordered eating behavior through its receptors in these areas of the central nervous system through the blood–brain barrier. There have been many studies of the association between AN and ghrelin, but in those studies the measured variables were total ghrelin, which included acyl ghrelin and des-acyl ghrelin. Acyl ghrelin and des-acyl ghrelin are thought to have opposite effects; that is, acyl ghrelin stimulates food intake and gut motility [5], and des-acyl ghrelin has been shown to significantly decrease food intake in food-deprived mice and decrease gastric emptying [30]. In some studies, des-acyl ghrelin has been reported to oppose acyl ghrelin-induced hyperphagic effects [31] and to block the stimulatory effects on food intake induced by acyl ghrelin [32]. These results indicate that acyl ghrelin and des-acyl ghrelin interact with each other. Considering the association between acyl ghrelin and des-acyl ghrelin, it is very important to measure these forms separately. However, a few reports have referred to the association between ghrelin forms and AN (Table 2) [33–37]. Hotta et al. [33] showed that plasma des-acyl ghrelin levels are significantly higher in patients with AN than in controls, and plasma acyl ghrelin levels tend to be slightly higher in patients with AN than in controls without a significant difference. Other
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Table 1 Plasma total ghrelin levels in patients with AN References
Subtype of ED
n
Total ghrelin level
Method of measurement
Janas-Kozik et al., 2007 [14] Tanaka et al., 2003 [20]
AN-R AN-R AN-BP AN-R AN-BP AN-R AN-BP AN AN AN AN-R AN-BP AN AN AN AN-R AN-BP AN AN ED AN-R AN-BP BN-P
30 19 20 14 13 21 19 5 20 8 13 2 19 22 6 19 20 9 36 11 3 6 2
AN-R > control AN-BP > AN-R >control
RIA RIA
AN-R > control AN-BP > control AN-R > control AN-BP > control AN > control AN > control AN > control AN > control
RIA
RIA ELISA RIA RIA
AN > control AN > control AN > control AN-BP > AN-R >control
RIA RIA RIA RIA
AN > control AN > control ED > control
RIA RIA RIA
Tanaka et al., 2004 [21] Tanaka et al., 2003 [15] et al., 2003 [22] Nedvıdkova Monteleone et al., 2008 [18] Sedlackova et al., 2010 [19] Troisi et al., 2005 [16] Misra et al., 2004 [23] Misra et al., 2005 [24] Rigamonti et al., 2002 [25] Tanaka et al., 2003 [26] Tolle et al., 2003 [27] Otto et al., 2001 [28] Uehara et al., 2005 [17]
RIA
AN, anorexia nervosa; AN-BP, anorexia nervosa binge-eating/purging type; AN-R, anorexia nervosa restricting type; BN-P, bulimia nervosa purging type; ED, eating disorder; ELISA, enzyme-linked immunosorbent assay; RIA, radioimmunoassay
studies have demonstrated similar results [34–36]. Koyama et al. [34] suggested that plasma des-acyl ghrelin levels in patients with AN-R start decreasing very rapidly after body weight has been regained through treatment, suggesting that des-acyl ghrelin is altered in a manner that depends on nutritional status. Considering the roles of acyl ghrelin and des-acyl ghrelin, not only are the absolute levels but also the ratio of these forms are very important (Table 2). Hotta et al. [33] showed that the ratio of des-acyl ghrelin to acyl ghrelin is higher in patients with AN than in controls. Nakahara et al. [36] also demonstrated a high ratio of acyl ghrelin to des-acyl ghrelin in patients with AN. In other studies, the ratio of des-acyl ghrelin to acyl ghrelin in patients with AN-R has tended to be higher than in controls when estimating their results (statistical differences were not known) [33, 35,37]. However, the ratio of acyl ghrelin to total ghrelin has not significantly different between patients with AN and controls [17, 34]. These results imply that increased des-acyl ghrelin levels might prevent patients with AN from eating and thus gaining body weight. Recently, ghrelin O-acyltransferase (GOAT) was identified as the endogenous key enzyme responsible for ghrelin acylation. Müller et al. [38] showed that the G/G genotype at single nucleotide polymorphism (SNP) rs10096097 might be associated
with AN and that homozygous risk G-allele carriers may have an increased risk for AN. Although the potential implication of SNPs for AN remains unknown, loss-of-function mutations in GOAT might disturb the ratio of acyl ghrelin to des-acyl ghrelin and might lead to impaired eating behavior. Obestatin has also been reported to increase in patients with AN. Harada et al. [35] showed that plasma obestatin levels in AN-R are higher than in controls. Nakahara et al. [36] also demonstrated that plasma obestatin levels are higher in patients with AN and lower in obese patients than in controls. They suggested that obestatin is a nutritional marker reflecting body adiposity and insulin resistance. However, plasma obestatin levels in patients with AN were higher than in constitutionally thin women who were matched for body mass index and in whom obestatin levels were similar to those in control groups without significant differences [39]. Monteleone et al. [18] indicated that plasma obestatin levels are increased in patients with AN but not in those with BN compared with control groups. Sedlackova et al. [19] also demonstrated that fasting plasma obestatin levels are increased in patients with AN and with BN but are higher in patients with AN than in those with BN. They suggested that different fasting obestatin levels in AN and BN could demonstrate their diverse functions in appetite and eating
Table 2 Plasma acyl/des-acyl ghrelin levels and ratio in patients with AN References
Subtype of ED
n
Acyl ghrelin
Des-acyl ghrelin
Des-acyl/acyl ghrelin ratio
Method of measurement
Hotta et al., 2004 [33]
AN
30
Koyama et al., 2010 [34] Harada et al., 2008 [35] Nakahara et al., 2008 [36] Ogiso et al., 2011 [37]
AN-R AN-R AN AN-R
5 10 11 7
AN > controly AN > control AN-R > controly AN-R > controly AN > controly AN-R > control
AN > control d AN-R > control AN-R > control AN > control AN-R > control
6.14 (AN) > 3.34 (control) d 14.5 (AN-R) > 11.5 (control)* 11.9 (AN-R) > 10.3 (control)* 12.7 (AN) > 10.1 (control) 4.8 (AN-R) > 3.9 (control)*
ELISA RIA ELISA ELISA ELISA ELISA
AN, anorexia nervosa; AN-R, anorexia nervosa restricting type; ED, eating disorder; ELISA, enzyme-linked immunosorbent assay; RIA, radioimmunoassay * The des-acyl/acyl ghrelin ratio was estimated by dividing the mean acyl ghrelin level by the mean des-acyl ghrelin level, and significant differences were unknown because there were not shown in the original reports. y Plasma acyl ghrelin levels in the AN or AN-R group tended to be higher than in the control group in each study, but there were no significant differences between the AN or AN-R group and the control group (P > 0.05).
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suppression. In addition, Germain et al. [40] recently demonstrated that total and acylated ghrelin and obestatin circadian levels are increased in patients with AN-R compared with controls but decreased in patients with AN binge-eating/purging type and those with BN. The assessment of these peptides may help in revealing the differences in eating behavior between ANR and AN binge-eating/purging type. Further research is needed because there are few reports of an association between AN and obestatin compared with ghrelin. Collectively in these results, plasma total ghrelin and acyl ghrelin levels in patients with AN were higher than in controls, and the ratio of des-acyl ghrelin to acyl ghrelin in AN tended to be higher than in controls. Des-acyl ghrelin has been found to disrupt fasted motility in the antrum [10] and oppose acyl ghrelin-induced hyperphagic effects [31,32]. These findings suggest that the tendency of increasing plasma des-acyl ghrelin levels in patients with AN may contribute to the etiology of AN through the interaction between acyl ghrelin and des-acyl ghrelin. It is very important to measure acyl ghrelin and des-acyl ghrelin separately in patients with AN for further investigations.
Clinical application of ghrelin Intravenous infusion of ghrelin has been reported to increase food intake and body weight in healthy subjects [41] and to stimulate appetite and food intake in patients with chronic heart failure, chronic obstructive pulmonary disease, and cancer [42–44]. With respect to the effects of acyl ghrelin, such as stimulating food intake and gut motility, ghrelin is expected to be effective in AN because chronic malnutrition induces functional and organic changes in the GI tract [12,13]. Hotta et al. [45] demonstrated that the intravenous administration of ghrelin in patients with AN-R twice a day for 14 d improves epigastric discomfort or constipation and increases the hunger score, which is related to gastric emptying. Although the increases of body weight in patients with AN was 1.5 to 2.4 kg, daily energy intake during ghrelin infusion increased by 12% to 36% compared with the pretreatment period. These results imply that ghrelin has the potential as a new treatment for AN. In Japan, a phase 3 clinical study with intravenous ghrelin in patients with AN is underway, which could address whether and how normalization of the feeding–regulatory circuitry corrects metabolic, GI, and behavioral abnormalities of these patients. In contrast, although Miljic et al. [46] reported that singledose continuous administration of ghrelin in patients with AN for 5 h failed to affect appetite, further investigations are needed such as long-term and repeated administration because this study was designed to administer ghrelin in a single dose. Anorexia nervosa is considered a complex multifactorial disease, including the diversity of psychosocial problems. Ghrelin will be effective in patients with AN complaining of symptoms such as upper abdominal discomfort because ghrelin increases gut motility. Therefore, it may be important to select the patients with AN with decreased gut motility and complaints of abdominal discomfort in clinical studies. Moreover, long-term administration would be needed to evaluate the effect of ghrelin on gaining body weight because a 1-kg weight gain requires 7000 to 8000 kcal. If the clinical trials were designed to administer ghrelin for a long-term period to patients with AN complaining of abdominal discomfort, the effect of ghrelin in patients with AN would become increasingly apparent. Further studies are required to clarify the therapeutic potential of ghrelin in patients with AN.
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More recently, Barnett et al. [47] demonstrated that the administration of a GOAT inhibitor improves glucose tolerance and decreases weight gain in wild-type mice but not in ghrelindeficient mice. These results indicate that a GOAT inhibitor might be expected to help pave the way for clinical targeting of GOAT in metabolic diseases such as obesity and diabetes mellitus. Conversely, a GOAT activator, which has not been reported yet, may be a potential new treatment of AN if it improves food intake and body weight gain in patients with AN. A psychosomatic perspective Brain–gut peptides may be important not only in the regulation of feeding and metabolism but also in other neuroendocrine and behavior functions. Previously, some studies have demonstrated an association between brain–gut peptides and feeding behavior using fMRI and SNPs. For instance, using fMRI, peptide YY, a physiological gut-derived satiety signal, has been found to modulate the activity of the OFC and other corticolimbic and higher cortical regions, independently of meal-related sensory experiences. Peptide YY modulation of cortical and hypothalamic brain areas predicts feeding behavior in humans. As a result, rewarding aspects of food are decreased by peptide YY modulation of OFC [48]. Similarly, using fMRI, leptin replacement in genetically leptin-deficient adults has been found to decrease brain activation in regions linked to hunger (insula and parietal and temporal cortices) and simultaneously increase activation in regions linked to inhibition and satiety (prefrontal cortex) during viewing of food-related stimuli [49]. Ghrelin administrated intravenously to healthy volunteers during fMRI has been found to increase the neural response to food pictures in regions of the brain, including the amygdala, OFC, anterior insula, and striatum, implicated in encoding the incentive value of food cues. The effects of ghrelin on the amygdala and OFC response have been correlated with self-rated hunger ratings. This demonstrates that metabolic signals such as ghrelin may favor food consumption by increasing the hedonic and incentive responses to food-related cues [7]. The SNPs of brain–gut peptides have been thought to affect feeding behavior. The mutation of melanocortin-4 receptor, which is related to anorexigenic signals, has led to hyperphagia, hyperinsulinemia, and increased lean body mass [50]. NPY is important not only in stimulating food intake but also in anxiolytic peptides, which are released by stress. A SNP located in the promoter region alters NPY expression, suggesting that genetic variation in human NPY expression affects stress response and emotion [51]. These investigations using fMRI and SNPs support the idea that brain–gut peptides may play a role in feeding behaviors in humans. Indeed, several SNPs of the ghrelin gene have been found, which is associated with AN bingeing/purging subtype or BN, supporting the hypothesis that ghrelin polymorphism may increase susceptibility to binge eating [52,53]. Recently, the autoantibodies against feeding–regulatory peptides such as a-melanocyte–stimulating hormone in patients with AN and BN have been reported, with serum levels being correlated with psychopathologic traits in these patients [54]. In patients with AN, the levels of immunoglobulin G of autoantibodies reactive with acyl ghrelin decreased. Immunoglobulin G autoantibodies exist mainly as an immune complex with desacyl ghrelin accompanied by a decrease of a free fraction of these autoantibodies binding acyl and des-acyl ghrelin levels. This decrease of bioavailable ghrelin autoantibodies may underlie a long-term increase of plasma ghrelin levels and the resulting phenomenon of ghrelin resistance in malnourished patients
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with AN [55]. The autoantibodies could alter the feeding– regulatory circuitry and behavior by changing the signaling of the molecule ranging from transport to neutralization. The “mixed” signal about satiety and desire to feed could contribute to the ambivalence about food, the dissociation that anorexics often display between decreased caloric intake and obsessive thoughts about food [1,2]. This mixed signal could underlie bulimic binging behavior in which a relative decrease in anorexigenic signaling is characteristic, as is an obsessional preoccupation with body weight and body shape, an aversively conditioned learning. Ghrelin secretion in AN is amplified in its cephalic phase as in other GI hormones and may aim to counteract the patients’ rigid control over their food intake, eventually facilitating binge-eating behavior [56]. Additional investigations of the relations between brain–gut peptides and feeding behavior using new techniques, such as fMRI, SNPs, and autoantibodies, would help elaborate on the psychopathology. Conclusion Acyl ghrelin, des-acyl ghrelin, and obestatin derived from alternative splicing or extensive post-translational modifications of preproghrelin may be part of a system with multiple effector elements and form the basis of an integrated gut–brain axis modulating appetite and behavior. Ghrelin peptides may have a role in feeding behavior, adaptation to starvation, reward mechanisms, emotional behavior, and stress responses in animals and humans. Neuroimaging studies have suggested ventral and dorsal neural circuit dysfunctions in patients with eating disorders, with altered metabolisms of serotonin and dopamine that are closely associated to ghrelin, contributing to their puzzling symptoms [57]. More sophisticated analyses are needed to assess the central nervous system activity of ghrelin signaling in humans and to identify the specific pathways that may underlie the pathologic behaviors in patients with AN. However, the investigation of the ghrelin peptide system will open up a new opportunity for tackling psychosomatic disorders beyond the GI tract, particularly anorexia/cachexia syndrome and obesity/metabolic syndrome, two disorders at the extreme of the body weight continuum. References [1] Kaye WH, Bulik CM, Thornton L, Barbarich N, Masters K. Comorbidity of anxiety disorders with anorexia and bulimia nervosa. Am J Psychiatry 2004;161:2215–21. [2] Inui A. Eating behavior in anorexia nervosadan excess of both orexigenic and anorexigenic signaling? Mol Psychiatry 2001;6:620–4. [3] Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone–releasing acylated peptide from stomach. Nature 1999;402:656–60. [4] Inui A. Ghrelin: An orexigenic and somatotrophic signal from the stomach. Nat Rev Neurosci 2001;2:551–60. [5] Chen CY, Asakawa A, Fujimiya M, Lee SD, Inui A. Ghrelin gene products and the regulation of food intake and gut motility. Pharmacol Rev 2009;61:430–81. [6] Depoortere I. Targeting the ghrelin receptor to regulate food intake. Regul Pept 2009;156:13–23. [7] Malik S, McGlone F, Bedrossian D, Dagher A. Ghrelin modulates brain activity in areas that control appetitive behavior. Cell Metab 2008;7:400–9. [8] Abizaid A, Liu ZW, Andrews ZB, Shanabrough M, Borok E, Elsworth JD, et al. Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite. J Clin Invest 2006;116:3229–39. [9] Diano S, Farr SA, Benoit SC, McNay EC, da Silva I, Horvath B, et al. Ghrelin controls hippocampal spine synapse density and memory performance. Nat Neurosci 2006;9:381–8. [10] Chen CY, Inui A, Asakawa A, Fujino K, Kato I, Chen CC, et al. Des-acly ghrelin acts by CRF type 2 receptors to disrupt fasted stomach motility in conscious rats. Gastroenterology 2005;129:8–25.
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