Alessandra Donzelli Fabbri1, Sophie Deram1, Daniel Shikanai Kerr2, Táki Athanássios Cordás3
1 Eating Disorders Program (Ambulim) at the Institute of Psychiatry, of the Hospital das Clinicas of the School of Medicine of University of Sao Paulo (IPq-HC-FMUSP), Sao Paulo, SP, Brazil.
2 Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry of the FMUSP, Sao Paulo, SP, Brazil.
3 IPq-HC-FMUSP, Sao Paulo, SP, Brazil.
Received: 2/11/2015 – Accepted: 3/4/2015
Address correspondence to: Alessandra Donzelli Fabbri. Rua Ovídio Pires de Campos, 785, 1º andar, sala 8 – 05403-010 – São Paulo, SP, Brazil. Email: firstname.lastname@example.org
Background: Ghrelin is a potent hormone with central and peripheral action. This hormone plays an important role in the regulation of appetite, food intake, and energy balance. Studies have suggested that ghrelin is involved with eating disorders (ED), particularly bingeing and purging. Genetic variants have also been studied to explain changes in eating behavior. Methods: We conducted a literature review; we searched PubMed, Scientific Electronic Library Online (SciELO), and LILACS databases using the keywords “eating disorder”, “ghrelin”, “polymorphism”, “anorexia nervosa”, “bulimia nervosa”, “binge eating disorder”, and their combinations. We found 319 articles. Thirty-nine articles met the inclusion criteria. Results: High levels of ghrelin were found in patients with anorexia nervosa (AN), especially in the purging subtype (AN-P). There was also a positive correlation between fasting ghrelin level and frequency of episodes of bingeing/purging in bulimia nervosa (BN) and the frequency of bingeing in periodic binge eating disorder (BED). Some polymorphisms were associated with AN and BN. Conclusion: Changes in ghrelin levels and its polymorphism may be involved in the pathogenesis of EDs; however, further studies should be conducted to clarify the associations.
Fabbri AD et al. / Arch Clin Psychiatry. 2015;42(2):52-62
Keywords: Eating disorders, ghrelin, ghrelin receptors, single nucleotide polymorphism, genetics.
Eating disorders (ED) are characterized by severe changes in eating behavior1-3. Anorexia nervosa (AN), bulimia nervosa (BN) and binge eating disorder (BED) are EDs known for their high morbidity and mortality affecting mostly adolescents and young adult females and can lead to major biological, psychological and social complications4-7. AN is characterized by intense fear of weight gain, severe food restriction, low body weight and a distorted perception of the body image. BN is characterized by episodes of binge eating (uncontrolled consumption of a large amount of food in a short period of time) followed by inappropriate compensatory behaviors aimed at preventing weight gain (such as: self-induced vomiting, abuse of laxatives, diuretics, amphetamines and/or excessive physical activity), these episodes must occur at least once per week for three months. Finally, BED is characterized by episodes of binge eating as described previously but without the use of compensatory methods, as frequently quoted in BN2,6.
Studies indicate a prevalence of ED ranging from 0.4% to 1.6%, with the highest frequency found in young women (between 18 and 32 years old)2,4. In Brazil, there is still a scarce number of epidemiological studies involving ED, even if the number of these studies has increased in recent years8.
The etiology of an ED is complex and although widely studied, is still poorly understood. It is believed that the disease is multifactorial with a complex interaction of several factors: biological, psychological, sociocultural and family-related which are responsible for initiating and maintaining ED9-11. There is substantial evidence that genetic factors have up to an 80% stake in the etiology of AN12, however, little is known about the molecular mechanism of these cases13.
Most genetic studies on ED are focused on the investigation of candidate genes. Several genes that play an important role in appetite regulation and satiety are considered candidates and may be related to the development of ED14-18, but the results of these studies are still inconsistent19,20.
One of the major hormones involved in the regulation of food intake is ghrelin. Although there are many neuropeptides that stimulate food intake, ghrelin is the most established orexigenic peptide known until now21.
We conducted a literature review to human studies in PubMed, Scientific Electronic Library Online (SciELO) and Lilacs databases, published between January 2000 and December 2014. The main keywords were used: “eating disorder” and “ghrelin”, and filtered the results to the terms: “anorexia nervosa”, “bulimia nervosa”, “binge eating disorder”, “polymorphism” and their combinations. The inclusion criteria were: 1) articles in English, Portuguese and Spanish; 2) articles that fully approached the topic ghrelin, eating disorders and their possible biological/genetic changes; 3) only studies in patients with diagnoses AN, BN and BED.
Three hundred and nineteen articles were found and only 39 contemplated these criteria (5 review articles, meta-analysis 1 and 33 experimental articles). Review articles and meta-analysis on the subject were consulted and cited in the discussion of this review, but for the presentation of data only original articles were used. We excluded studies in other languages and case reports as well, as articles that exclusively broached the topic obesity and ghrelin.
The synthesis of these studies is presented in tables 1 and 2, sorted by month and year of publication. All data were taken from the original articles. To facilitate comparison we standardized the display of age and BMI and consider only one house after the comma without rounding.
Ghrelin and the regulation of appetite
The arcuate nucleus (ARC) of the hypothalmus and the brain stem are important regions involved in the regulation of appetite, body weight and energy balance22. The variety of hypothalamic appetite regulators are divided into two groups: The orexigenic types (appetite stimulators) which include the neuropeptide Y (NPY), the agouti-related peptide (AgRP), ghrelin, orexin and cannabinoids, while the anorectics (appetite suppressants) which include pro-opiomelanocortin (POMC), and cocaine and amphetamine regulated transcript (CART), thyrotropin releasing hormone (TRH), corticotropin releasing hormone (CRH), peptide YY (PYY), cholecystokinin (CCK) and glucagon-like-peptide (GLP 1), among other23.
Ghrelin is a peptide of 28 amino acids, synthesized mainly by the oxyntic glands of the stomach24. It is acylated in the third residue which is a serine, the introduction of fatty acid (n-octanoyl) is essential for its activity25.
It is one of the major signaling mechanisms for the start of the meal26. In humans, its concentration stays high during periods of fasting and periods that precede meals, falling soon after the start of food intake27,28.
It is also involved in stimulating the secretion of growth hormone (GH) via the endogenous ligand of the GH secretagogue receptor (GHS-R)29. There are two subtypes of receptors, GHS-R1a, which is active, and GHS-R1b, a smaller isoform, which apparently has no biological activity30. This receptor (GHS-R) is present in various tissues including the anterior hypophysis and the hypothalamus, and in other areas of the brain, such as the hippocampus and gray matter. Because of its location, it has been suggested that GHS-R can modulate biological rhythms, mood, memory, learning and appetite31.
Ghrelin is an orexigenic hormone that acts on the Central Nervous System (CNS) by activating the NPY/AgRP32 neurons in the ARC via the GHS-R receptor. Thus, it promotes the production and secretion of other orexigenic neuropeptides that suppress neuronal activity of the POMC/CART, while stimulating food intake33, this hormone undergoes a process of acetylation required to bypass the blood-brain barrier, making it suitable to connect to the GHS-R1a34. This acetylation converts the desacyl ghrelin (inactive form) into acyl ghrelin (active form)35 and is catalyzed by the enzyme ghrelin O-acyltransferase (GOAT)25 (Figure 1).
Ghrelin in EDs
The role of ghrelin has been extensively investigated in the etiology of obesity and contrary to what was expected, plasma levels seem to have an inverse correlation with the body mass index (BMI)28,36. Studies have shown that ghrelin levels are lower in obese subjects as compared to control subjects36-39. One study noted that the decrease in ghrelin after the meal was lower in obese individuals compared to normal weight individuals40, and can thereby maintain the feeling of hunger. Studies with obese children also found low plasma ghrelin levels41,42 and when these children have reduced 50% of their BMI, ghrelin levels remained lower in comparison to control subjects41. The same finding was observed in obese adults who normalized their BMI43,44.
Studies conducted with AN patients found high levels of ghrelin in the plasma of these patients when compared with control of normal-weight individuals39,45-49 which may suggest that this change may be an adaptive response to prolonged starvation50. Tolle et al. compared the levels of ghrelin plasma in 3 groups: healthy women considered thin (CT), who had a BMI similar to women with AN; patients with AN and women with normal weight (NW)51. It was demonstrated that ghrelin plasma concentrations in fasting patients with AN, was increased and remained high throughout the day (measured every 4 hours over a period of 24 hours) as compared to CT and NW. The study noted that these levels normalized after the patient gained the weight back, suggesting that in addition to body weight, levels of ghrelin may also be affected by the nutritional state51. Body fat instead of BMI has best explained the changes in the levels of ghrelin47, some of the groups that had contradictory results between the correlation of BMI and ghrelin showed consistent results for body fat37,45,52-54. Studies have shown that ghrelin levels in patients with AN Restrictive (AN-R) have not been fully standardized, even after treatment41,55-58.
Differences in ghrelin levels between subtypes of AN have also been reported. Tanaka et al. in 2003 found higher plasma levels of ghrelin in patients with AN Purging (AN-P) than in AN-R59-61. In 2004, the group of Tanaka replicated their findings in a later study which included a third subgroup of AN, a subgroup that required emergency hospitalization; in this group the patients were unable to eat and had an extreme loss of weight. It showed that the emergency group had higher plasma levels of ghrelin than AN-P, and that AN-P still had levels greater than the AN-R levels. The three groups experienced a decrease in their plasma levels of ghrelin after treatment, but patients with AN-P still kept the plasma levels of ghrelin higher than the control group at the end of rehabilitation62. In 2005 Troisi et al., found higher levels of ghrelin during fasting in AN-R patients when compared to the AN-P patients63. However, the Troisi group compared data between patients with AN-P and BN, which probably had a higher BMI, which may explain the difference between the results of the two studies. There seems to be a relationship between ghrelin concentrations and patients with the compulsive/purging subtype for both AN (AN-P) and for BN59-61. However, this finding has still not reached a consensus, Monteleone et al. 200847 found no significant difference in the concentration of plasma ghrelin when fasting in groups with AN-R and AN-P. One explanation for these conflicting results is the method used to measure ghrelin and how it was performed, the preference for using plasma or serum can affect the levels obtained in different studies. The Monteleone study has confirmed this hypothesis; the study in 2008 obtained the result by screening for ghrelin plasma by way of the ELISA method (enzyme-linked immunosorbent assay). Whereas in 201064, in order to study patients with BN, they used the same test used by the group of Tanaka in 2003: the RIA (Radioimmunoassay) method and observed similar results, higher levels of ghrelin in these patients as compared to controls.
Tanaka et al. 200254 and Kojima et al. 200565, also observed elevated levels of fasting ghrelin in patients with BN. In addition, Tanaka in 2002 noted that ghrelin levels were negatively correlated with BMI and body fat percentage in both BN, as in the control group54. On the other hand, Nakazato et al. in 2004 found no significant difference between the levels of ghrelin plasma in patients with BN and the control group66. One possible explanation for this would be that Nakazato et al. 2004 measured ghrelin levels in the serum randomly between 11:00 am-12: 00 pm (postprandially), unlike Tanaka et al. 2002 who measured when fasting. When Kojima in 2005 measured the pre-and postprandial ghrelin, it was noted that the decrease in postprandial ghrelin was significantly attenuated in women with BN compared to the control group66,67, generating a possible delay in the reduction of the hunger sensation in these patients.
Patients with BED tend to show a decrease in ghrelin when fasting53,63,68 and a lower postprandial decline compared to the obese control group68. This decrease in ghrelin does not seem to reduce the propensity to gain weight in BED patients. Low ghrelin levels were also found in obese patients and seem to be more related to a sub-regulation of the release of ghrelin in response to excess weight and a lower postprandial decline, possibly acting to maintain the hunger21.
A meta-analysis in 2009 found plasma concentrations in fasting and postprandial appetite hormones (gut hormones) in patients with AN, BN subtypes. It observed that in 8 studies analyzed, seven found elevated levels of plasma ghrelin in all diagnoses, with the exception of a single study69.
In conclusion, the studies suggest that the changes found in ghrelin may be more related to the behavior of the binging and purging60. However, for the time being, it is still not clear as per whether ghrelin fundamentally participates as an important factor in the etiology of the EDs70.
Ghrelin and the genes
The human ghrelin gene (GHLR, Gene ID: 51738)71 which encodes ghrelin is located in the short arm of the chromosome 3 (3p25-26)33. Initially it was thought that it would have 4 exons (coding part of the gene), but subsequent studies have identified a number of additional exons in humans72. The precursor to ghrelin, the pre-proghrelin, is formed in the post-transcriptional process of GHLR, it consists of 518 pb encoded in a sequence of 117 amino acids, distributed over 23 amino acids of the signal peptide and 94 amino acids of pro-ghrelin, which include 28 amino acids of the mature ghrelin and over 66 additional amino acids73, which include 23 of obestatin (a hormone with the antagonistic characteristics of ghrelin, which suppresses appetite and stomach activity)74. Therefore, ghrelin and obestatin are encoded by the same precursor gene (Figure 2).
The gene of the receptor (GHS-R, Gene ID: 2693)71 was also located in the chromosome 3 (3q-26-31)31. The gene consists of two exons separated by one intron (non-coding part of the gene) (Figure 3). The exon 1 encodes the I-V transmembrane regions and exon 2 encodes the regions VI and VII75. The GHS-R gene encodes two types of mRNA: GHS-R1a and GHS-R1b73. The GHS-R 1a contains all 7 transmembrane regions and possess a high affinity with ghrelin, while the physiological role of GHS-R1b is not yet entirely clear76.
The gene of GOAT (MBOAT4; Gene ID: 619373)71 is located in the chromosome 8 (8p12) and is expressed mainly in the stomach, in the pancreas and in lower concentrations in the bones77,78. This gene represents a new candidate gene in genetic research for investigating complex phenotypes70 (Figure 4).
In table 2 below, you can see some studies that investigated single nucleotide polymorphisms (SNPs) in the ghrelin gene, in individuals with a diagnosis of an ED. It is noticeable that the studies were still inconclusive when the GHRL gene is investigated, these studies show different positive and negative associations with different EDs diagnoses73,81,82,84,86. However, when they analyzed the genes of the GHS-R and of the GOAT some studies have found a positive association between polymorphisms and the EDs79. In this sense, only two studies have found a positive association between polymorphisms in the GHS-R and in the GOAT with BN and AN respectively, which is that of Miyasaka et al. 200683 and Muller et al. 201085.
In recent years, ghrelin has been an object of study in the EDs, but we haven’t had any clear conclusions about its role in these pathologies. Genetic research could bring a different perspective and provide a new direction for research.
The studies suggest that some polymorphisms in the ghrelin gene, mainly in the genes of GHS-R and the GOAT, may be involved in the pathogenesis of the EDs and possibly related to the behavior of binge eating and purging. However, this is a case of only two studies, further work should be conducted with larger samples addressing the need to compare the polymorphisms found between the three main types of eating disorders (AN, BN and BED) in order for greater clarity in the associations.
We give thanks to Alzira Denise Hertzog Silva for the cooperation in this review of the Laboratory of Neurosciences (LIM-27), Department and Institute of Psychiatry of FMUSP, São Paulo, SP.
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