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Ghrelin and eating disorders

Abstract

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.

Eating disorders; ghrelin; ghrelin receptors; single nucleotide polymorphism; genetics


Introduction

Eating disorders (ED) are characterized by severe changes in eating behavior1American Psychiatry Association (APA). Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (Washington DC): APA Press; 2000.

American Psychiatry Association (APA). Diagnostic and Statistical Manual of Mental Disorders (DSM-V) (Washington DC): APA Press; 2013.
-3Organização Mundial de Saúde (OMS). Classificação de Transtornos Mentais e do Comportamento da CID-10. Descrições clínicas e diretrizes diagnósticas. Porto Alegre: Artes Médicas; 1993.. 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 complications4American Dietetic Association (ADA). Position of the American Dietetic Association: Nutrition intervention in the treatment of anorexia nervosa, bulimia nervosa, and other eating disorders. J Am Diet Assoc. 2006;106(12):2073-82.

Cordás TA, Salzano FT. Aspectos gerais dos transtornos alimentares: características, critérios diagnósticos, epidemiologia e etiologia. In: Alvarenga M, Scagliusi FB, Phillippi ST. Nutrição e transtornos alimentares: avaliação e tratamento (Barueri): Manole; 2011. p. 5-15.

Pinzon V, Nogueira CF. Epidemiologia, curso e evolução dos transtornos alimentares. Rev Psiq Clin. 2004;31(4):158-60.
-7Cordás TA, Claudino AM. Transtornos alimentares: fundamentos históricos. Rev Bras Psiq. 2002;24(3):3-6.. 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 BN2American Psychiatry Association (APA). Diagnostic and Statistical Manual of Mental Disorders (DSM-V) (Washington DC): APA Press; 2013.,6Pinzon V, Nogueira CF. Epidemiologia, curso e evolução dos transtornos alimentares. Rev Psiq Clin. 2004;31(4):158-60..

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)2American Psychiatry Association (APA). Diagnostic and Statistical Manual of Mental Disorders (DSM-V) (Washington DC): APA Press; 2013.,4American Dietetic Association (ADA). Position of the American Dietetic Association: Nutrition intervention in the treatment of anorexia nervosa, bulimia nervosa, and other eating disorders. J Am Diet Assoc. 2006;106(12):2073-82.. In Brazil, there is still a scarce number of epidemiological studies involving ED, even if the number of these studies has increased in recent years8do Vale AM, Kerr LR, Bosi ML. Risk behaviors for eating disorders among female adolescents from different social strata in the Brazilian Northeastern. Cien Saude Colet. 2011;16(1):121-32..

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 ED9Morgana CM, Vecchiattia IR, Negrão AB. Etiologia dos transtornos alimentares: aspectos biológicos, psicológicos e sócio-culturais. Rev Bras Psiq. 2002;24(3):18-23.

10 Jacobi C, Hayward C, de Zwaan M, Kraemer HC, Agras WS. Coming to terms with risk factors for eating disorders: application of risk terminology and suggestions for a general taxonomy. Psychol Bull. 2004;130(1):19-65.
-1111 Dalle Grave R. Eating disorders: progress and challenges. Eur J Intern Med. 2011;22(2):153-60.. There is substantial evidence that genetic factors have up to an 80% stake in the etiology of AN1212 Bulik CM, Sullivan PF, Wade TD, Kendler KS. Twin studies of eating disorders: a review. Int J Eat Disord. 2000;27(1):1-20., however, little is known about the molecular mechanism of these cases1313 Klump KL, Miller KB, Keel PK, McGue M, Iacono WG. Genetic and environmental influences on anorexia nervosa syndromes in a population-based twin sample. Psychol Med. 2001;31(4):737-40..

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 ED1414 Hebebrand J, Remschmidt H. Anorexia nervosa viewed as an extreme weight condition: genetic implications. Human Genetics. 1995;95:1-11.

15 Pinheiro AP, Sullivan PF, Bacaltchuck J, Prado-Lima PA, Bulik CM. Genetics in eating disorders: extending the boundaries of research. Rev Bras Psiq. 2006;28:218-25.

16 Sulek S, Lacinová Z, Dolinková M, Haluzik M. Genetic polymorphisms as a risk factor for anorexia nervosa. Prague Med Rep. 2007;108:215-25.

17 Scherag S, Hebebrand J, Hinney A. Eating disorders: the current status of molecular genetic research. Eur Child Adolesc Psychiatry. 2010;19:211-26.
-1818 Smitka K, Papezova H, Vondra K, Hill M, Hainer V, Nedvidkova J. The role of “mixed” orexigenic and anorexigenic signals and autoantibodies reacting with appetite-regulating neuropeptides and peptides of the adipose tissue-gut-brain axis: relevance to food intake and nutritional status in patients with anorexia nervosa and bulimia nervosa. Int J Endocrinol. 2013;2013:4831-45., but the results of these studies are still inconsistent1919 Cellini E, Castellini G, Ricca V, Bagnoli S, Tedde A, Rotella CM, et al. Glucocorticoid receptor gene polymorphisms in Italian patients with eating disorders and obesity. Psychiatr Genet. 2010,20:282-8.,2020 Hinney A, Friedel S, Remschmidt H, Hebebrand J. Genetic risk factors in eating disorders. Am J Pharmacogenomics. 2004;4(4):209-23..

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 now2121 Atalayer D, Gibson C, Konopacka A, Geliebter A. Ghrelin and eating disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2013;40:70-82..

Methods

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.

Results

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.

Table 1
Studies of ghrelin plasma in differents EDs diagnoses, ordered by month and year of publication

Table 2
Studies of candidate genes for polymorphisms in the ghrelin gene (GHRL), the ghrelin O-acyltransferase (GOAT) and the GH secretagogue receptor (GHS-R) in EDs diagnoses

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 balance2222 Druce M, Bloom SR. The regulation of appetite. Arch Dis Child. 2006;91:183-7.. 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 other2323 Scerif M, Goldstone AP, Korbonits M. Ghrelin in obesity and endocrine diseases. Mol Cell Endocrinol. 2011;340:15-25..

Ghrelin is a peptide of 28 amino acids, synthesized mainly by the oxyntic glands of the stomach2424 Hebebrand J, Remschmidt H. Anorexia nervosa viewed as an extreme weight condition: genetic implications. Human Genetics. 1995;95:1-11.. It is acylated in the third residue which is a serine, the introduction of fatty acid (n-octanoyl) is essential for its activity2525 Yang J, Brown MS, Liang G, Grishin NV, Goldstein JL. Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell. 2008;132:387-96..

It is one of the major signaling mechanisms for the start of the meal2626 Cummings DE, Frayo RS, Marmonier C, Aubert R, Chapelot D. Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily without time- and food-related cues. Am J Physiol Endocrinol Metab. 2004;287:E297-304.. In humans, its concentration stays high during periods of fasting and periods that precede meals, falling soon after the start of food intake2727 Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes. 2001;50(8):1714-9.,2828 Tucci S. Grelina en regulación del apetito y papel en obesidad y trastornos alimentarios: Abordajes terapêuticos. Rev Venez Endocrinol Metab. 2008;6(2):15-23..

It is also involved in stimulating the secretion of growth hormone (GH) via the endogenous ligand of the GH secretagogue receptor (GHS-R)2929 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.. There are two subtypes of receptors, GHS-R1a, which is active, and GHS-R1b, a smaller isoform, which apparently has no biological activity3030 Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science. 1996;273:947-77.. 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 appetite3131 Smith RG, Van der Ploeg LHT, Howard AD, Feighner SD, Cheng K, Hickey GJ, et al. Peptidomimetic regulation of growth hormone secretion. Endocr Rev. 1997;18:621-45..

Ghrelin is an orexigenic hormone that acts on the Central Nervous System (CNS) by activating the NPY/AgRP3232 Seoane LM, Lopez M, Tovar S, Casanueva FF, Senaris R, Dieguez C. Agouti-related peptide, neuropeptide Y, and somatostatin-producing neurons are targets for ghrelin actions in the rat hypothalamus. Endocrinology. 2003;144:544-51. 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 intake3333 Cowley MA, Smith RG, Diano S, Tschop M, Pronchuk N, Grove KL, et al. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron. 2003;37:649-61., this hormone undergoes a process of acetylation required to bypass the blood-brain barrier, making it suitable to connect to the GHS-R1a3434 Hassouna R, Zizzari P, Tolle V. The ghrelin/obestatin balance in the physiological and pathological control of growth hormone secretion, body composition and food intake. J Neuroendocrinol. 2010;22(7):793-804.. This acetylation converts the desacyl ghrelin (inactive form) into acyl ghrelin (active form)3535 Hosoda H, Kojima M, Matsuo H, Kangawa, K. Ghrelin and des-acyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue. Biochem Biophys Res Commun. 2000;279:909-13. and is catalyzed by the enzyme ghrelin O-acyltransferase (GOAT)2525 Yang J, Brown MS, Liang G, Grishin NV, Goldstein JL. Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell. 2008;132:387-96. (Figure 1).

Figure 1
Ghrelin in its non-active form (desacyl ghrelin) being transformed into its active form (acyl ghrelin) by the enzyme ghrelin O-acyltransferase (GOAT). Adapted from Sato et al. 20128080 SatoT, Nakamura Y, Shiimura Y, Ohgusu H, Kangawa K, Kojima M. Structure, regulation and function of ghrelin. J Biochem. 2012;151(2):119-28..

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)2828 Tucci S. Grelina en regulación del apetito y papel en obesidad y trastornos alimentarios: Abordajes terapêuticos. Rev Venez Endocrinol Metab. 2008;6(2):15-23.,3636 Tschop M, Weyer C, Tataranni PA, Devanarayan, Ravussin E, Heiman ML. Circulating ghrelin levels are decreased in human obesity. Diabetes. 2001;50:707-9.. Studies have shown that ghrelin levels are lower in obese subjects as compared to control subjects3636 Tschop M, Weyer C, Tataranni PA, Devanarayan, Ravussin E, Heiman ML. Circulating ghrelin levels are decreased in human obesity. Diabetes. 2001;50:707-9.

37 Shiiya T, Nakazato M, Mizuta M, Date Y, Mondal MS, Tanaka M, et al. Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion. J Clin Endocrinol Metab. 2002;87:240-4.

38 Erdmann J, Lippl F, Wagenpfeil S, Schusdziarra V. Differential association of basal and postprandial plasma ghrelin with leptin, insulin, and type 2 diabetes. Diabetes. 2005;54:1371-8.
-3939 Stock S, Leichner P, Wong AC, Ghatei MA, Kieffer TJ, Bloom SR, et al. Ghrelin, peptide YY, glucose-dependent insulinotropic polypeptide, and hunger responses to a mixed meal in anorexic, obese, and control female adolescents. J Clin Endocrinol Metab. 2005;90(4):2161-8.. One study noted that the decrease in ghrelin after the meal was lower in obese individuals compared to normal weight individuals4040 English PJ, Ghatei MA, Malik IA, Bloom SR, Wilding JP. Food fails to suppress ghrelin levels in obese humans. J Clin Endocrinol Metab. 2002;87:2984., and can thereby maintain the feeling of hunger. Studies with obese children also found low plasma ghrelin levels4141 Soriano-Guillen L, Barrios V, Campos-Barros A, Argente J. Ghrelin levels in obesity and anorexia nervosa: effect of weight reduction or recuperation. J Pediatr. 2004;144:36-42.,4242 Wali P, King J, He Z, Tonb D, Horvath K. Ghrelin and obestatin levels in children with failure to thrive and obesity. J Pediatr Gastroenterol Nutr. 2014;58(3):376-81. and when these children have reduced 50% of their BMI, ghrelin levels remained lower in comparison to control subjects4141 Soriano-Guillen L, Barrios V, Campos-Barros A, Argente J. Ghrelin levels in obesity and anorexia nervosa: effect of weight reduction or recuperation. J Pediatr. 2004;144:36-42.. The same finding was observed in obese adults who normalized their BMI4343 Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med. 2002;346:1623-30.,4444 Hansen TK, Dall R, Hosoda H, Kojima M, Kangawa K, Christiansen JS, et al. Weight loss increases circulating levels of ghrelin in human obesity. Clin Endocrinol (Oxf). 2002;56:203-6..

Studies conducted with AN patients found high levels of ghrelin in the plasma of these patients when compared with control of normal-weight individuals3939 Stock S, Leichner P, Wong AC, Ghatei MA, Kieffer TJ, Bloom SR, et al. Ghrelin, peptide YY, glucose-dependent insulinotropic polypeptide, and hunger responses to a mixed meal in anorexic, obese, and control female adolescents. J Clin Endocrinol Metab. 2005;90(4):2161-8.,4545 Nedvidkova J, Krykorkova I, Bartak V, Papezova H, Gold PW, Alesci S, et al. Loss of meal-induced decrease in plasma ghrelin levels in patients with anorexia nervosa. J Clin Endocrinol Metab. 2003;88:1678-82.

46 Otto B, Cuntz U, Fruehauf E, Wawarta R, Folwaczny C, Riepl RL, et al. Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa. Eur J Endocrinol. 2001;145:669-73.

47 Monteleone P, Serritella C, Martiadis V, Scognamiglio P, Maj M. Plasma obestatin, ghrelin, and ghrelin/obestatin ratio are increased in underweight patients with anorexia nervosa but not in symptomatic patients with bulimia nervosa. J Clin Endocrinol Metab. 2008;93:4418-21.

48 Ariyasu H, Takaya K, Tagami T, Ogawa Y, Hosoda K, Akamizu T, et al. Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans. J Clin Endocrinol Metab. 2001;86(10):4753-8.
-4949 Misra M, Miller KK, Herzog DB, Ramaswamy K, Aggarwal A, Almazan C, et al. Growth hormone and ghrelin responses to an oral glucose load in adolescent girls with anorexia nervosa and controls. J Clin Endocrinol Metab. 2004;89(4):1605-12. which may suggest that this change may be an adaptive response to prolonged starvation5050 Yi CX, Heppner K, Tschöp MH. Ghrelin in eating disorders. Mol Cell Endocrinol. 2011;340(1):29-34.. 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)5151 Tolle V, Kadem M, Bluet-Pajot MT, Frere D, Foulon C, Bossu C, et al. Balance in ghrelin and leptin plasma levels in anorexia nervosa patients and constitutionally thin women. J Clin Endocrinol Metab. 2003;88:109-16.. 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 state5151 Tolle V, Kadem M, Bluet-Pajot MT, Frere D, Foulon C, Bossu C, et al. Balance in ghrelin and leptin plasma levels in anorexia nervosa patients and constitutionally thin women. J Clin Endocrinol Metab. 2003;88:109-16.. Body fat instead of BMI has best explained the changes in the levels of ghrelin4747 Monteleone P, Serritella C, Martiadis V, Scognamiglio P, Maj M. Plasma obestatin, ghrelin, and ghrelin/obestatin ratio are increased in underweight patients with anorexia nervosa but not in symptomatic patients with bulimia nervosa. J Clin Endocrinol Metab. 2008;93:4418-21., some of the groups that had contradictory results between the correlation of BMI and ghrelin showed consistent results for body fat3737 Shiiya T, Nakazato M, Mizuta M, Date Y, Mondal MS, Tanaka M, et al. Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion. J Clin Endocrinol Metab. 2002;87:240-4.,4545 Nedvidkova J, Krykorkova I, Bartak V, Papezova H, Gold PW, Alesci S, et al. Loss of meal-induced decrease in plasma ghrelin levels in patients with anorexia nervosa. J Clin Endocrinol Metab. 2003;88:1678-82.,5252 Monteleone P, Martiadis V, Fabrazzo M, Serritella C, Maj M. Ghrelin and leptin responses to food ingestion in bulimia nervosa: implications for binge-eating and compensatory behaviours. Psychol Med. 2003;33:1387-94.

53 Monteleone P, Fabrazzo M, Tortorella A, Martiadis V, Serritella C, Maj M. Circulating ghrelin is decreased in non-obese and obese women with binge eating disorder as well as in obese non-binge eating women, but not in patients with bulimia nervosa. Psychoneuroendocrinology. 2005a;30:243-50.
-5454 Tanaka M, Naruo T, Muranaga T, Yasuhara D, Shiiya T, Nakazato M, et al. Increased fasting plasma ghrelin levels in patients with bulimia nervosa. Eur J Endocrinol. 2002;146:R1-3.. Studies have shown that ghrelin levels in patients with AN Restrictive (AN-R) have not been fully standardized, even after treatment4141 Soriano-Guillen L, Barrios V, Campos-Barros A, Argente J. Ghrelin levels in obesity and anorexia nervosa: effect of weight reduction or recuperation. J Pediatr. 2004;144:36-42.,5555 Janas-Kozik M, Krupka-Matuszczyk I, Malinowska-Kolodziej I, Lewin-Kowalik J. Total ghrelin plasma level in patients with the restrictive type of anorexia nervosa. Regul Pept. 2007;140:43-6.

56 Nakahara T, Kojima S, Tanaka M, Yasuhara D, Harada T, Sagiyama K, et al. Incomplete restoration of the secretion of ghrelin and PYY compared to insulin after food ingestion following weight gain in anorexia nervosa. J Psychiatr Res. 2007;41:814-20.

57 Terra X, Auguet T, Agüera Z, Quesada IM, Orellana-Gavaldà JM, Aguilar C, et al. Adipocytokine levels in women with anorexia nervosa. Relationship with weight restoration and disease duration. Int J Eat Disord. 2013;46(8):855-6.
-5858 Otto B, Tschöp M, Frühauf E, Heldwein W, Fichter M, Otto C, et al. Postprandial ghrelin release in anorectic patients before and after weight gain. Psychoneuroendocrinology. 2005;30(6):577-81..

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-R5959 Tanaka M, Naruo T, Nagai N, Kuroki N, Shiiya T, Nakazato M, et al. Habitual binge/purge behavior influences circulating ghrelin levels in eating disorders. J Psychiatr Res. 2003a;37(1):17-22.

60 Tanaka M, Naruo T, Yasuhara D, Tatebe Y, Nagai N, Shiiya T, et al. Fasting plasma ghrelin levels in subtypes of anorexia nervosa. Psychoneuroendocrinology. 2003b;28(7):829-35.
-6161 Tanaka M, Tatebe Y, Nakahara T, Yasuhara D, Sagiyama K, Muranaga T, et al. Eating pattern and the effect of oral glucose on ghrelin and insulin secretion in patients with anorexia nervosa. Clin Endocrinol (Oxf). 2003c;59(5):574-9.. 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 rehabilitation6262 Tanaka M, Nakahara T, Kojima S, Nakano T, Muranaga T, Nagai N, et al. Effect of nutritional rehabilitation on circulating ghrelin and growth hormone levels in patients with anorexia nervosa. Regul Pept. 2004;122:163-8.. In 2005 Troisi et al., found higher levels of ghrelin during fasting in AN-R patients when compared to the AN-P patients6363 Troisi A, Di Lorenzo G, Lega I, Tesauro M, Bertoli A, Leo R, et al. Plasma ghrelin in anorexia, bulimia, and binge-eating disorder: relations with eating patterns and circulating concentrations of cortisol and thyroid hormones. Neuroendocrinology. 2005;81:259-66.. 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 BN5959 Tanaka M, Naruo T, Nagai N, Kuroki N, Shiiya T, Nakazato M, et al. Habitual binge/purge behavior influences circulating ghrelin levels in eating disorders. J Psychiatr Res. 2003a;37(1):17-22.

60 Tanaka M, Naruo T, Yasuhara D, Tatebe Y, Nagai N, Shiiya T, et al. Fasting plasma ghrelin levels in subtypes of anorexia nervosa. Psychoneuroendocrinology. 2003b;28(7):829-35.
-6161 Tanaka M, Tatebe Y, Nakahara T, Yasuhara D, Sagiyama K, Muranaga T, et al. Eating pattern and the effect of oral glucose on ghrelin and insulin secretion in patients with anorexia nervosa. Clin Endocrinol (Oxf). 2003c;59(5):574-9.. However, this finding has still not reached a consensus, Monteleone et al. 20084747 Monteleone P, Serritella C, Martiadis V, Scognamiglio P, Maj M. Plasma obestatin, ghrelin, and ghrelin/obestatin ratio are increased in underweight patients with anorexia nervosa but not in symptomatic patients with bulimia nervosa. J Clin Endocrinol Metab. 2008;93:4418-21. 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 20106464 Monteleone P, Serritella C, Scognamiglio P, Maj M. Enhanced ghrelin secretion in the cephalic phase of food ingestion in women with bulimia nervosa. Psychoneuroendocrinology. 2010;35:284-8., 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. 20025Cordás TA, Salzano FT. Aspectos gerais dos transtornos alimentares: características, critérios diagnósticos, epidemiologia e etiologia. In: Alvarenga M, Scagliusi FB, Phillippi ST. Nutrição e transtornos alimentares: avaliação e tratamento (Barueri): Manole; 2011. p. 5-15.4American Dietetic Association (ADA). Position of the American Dietetic Association: Nutrition intervention in the treatment of anorexia nervosa, bulimia nervosa, and other eating disorders. J Am Diet Assoc. 2006;106(12):2073-82. and Kojima et al. 20056565 Kojima S, Nakahara T, Nagai N, Muranaga T, Tanaka M, Yasuhara D, et al. Altered ghrelin and peptide YY responses to meals in bulimia nervosa. Clin Endocrinol (Oxf). 2005;62:74-8., 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 group5454 Tanaka M, Naruo T, Muranaga T, Yasuhara D, Shiiya T, Nakazato M, et al. Increased fasting plasma ghrelin levels in patients with bulimia nervosa. Eur J Endocrinol. 2002;146:R1-3.. 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 group6666 Nakazato M, Hashimoto K, Shiina A, Koizumi H, Mitsumoti M, Imai M, et al. No changes in serum ghrelin levels in female patients with bulimia nervosa. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28:1181-4.. 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 group6666 Nakazato M, Hashimoto K, Shiina A, Koizumi H, Mitsumoti M, Imai M, et al. No changes in serum ghrelin levels in female patients with bulimia nervosa. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28:1181-4.,6767 Monteleone P, Martiadis V, Rigamonti AE, Fabrazzo M, Giordani C, Muller EE, et al. Investigation of peptide YY and ghrelin responses to a test meal in bulimia nervosa. Biol Psychiatry. 2005b;57:926-31., 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 fasting5353 Monteleone P, Fabrazzo M, Tortorella A, Martiadis V, Serritella C, Maj M. Circulating ghrelin is decreased in non-obese and obese women with binge eating disorder as well as in obese non-binge eating women, but not in patients with bulimia nervosa. Psychoneuroendocrinology. 2005a;30:243-50.,6363 Troisi A, Di Lorenzo G, Lega I, Tesauro M, Bertoli A, Leo R, et al. Plasma ghrelin in anorexia, bulimia, and binge-eating disorder: relations with eating patterns and circulating concentrations of cortisol and thyroid hormones. Neuroendocrinology. 2005;81:259-66.,6868 Geliebter A, Gluck ME, Hashim SA. Plasma ghrelin concentrations are lower in binge-eating disorder. J Nutr. 2005;135:1326-30. and a lower postprandial decline compared to the obese control group6868 Geliebter A, Gluck ME, Hashim SA. Plasma ghrelin concentrations are lower in binge-eating disorder. J Nutr. 2005;135:1326-30.. 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 hunger2121 Atalayer D, Gibson C, Konopacka A, Geliebter A. Ghrelin and eating disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2013;40:70-82..

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 study6969 Prince AC, Brooks SJ, Stahl D, Treasure J. Systematic review and meta-analysis of the baseline concentrations and physiologic responses of gut hormones to food in eating disorders. Am J Clin Nutr. 2009;89(3):755-65..

In conclusion, the studies suggest that the changes found in ghrelin may be more related to the behavior of the binging and purging6060 Tanaka M, Naruo T, Yasuhara D, Tatebe Y, Nagai N, Shiiya T, et al. Fasting plasma ghrelin levels in subtypes of anorexia nervosa. Psychoneuroendocrinology. 2003b;28(7):829-35.. 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 EDs7070 Liu B, Garcia EA, Korbonits M. Genetic studies on the ghrelin, growth hormone secretagogue receptor (GHSR) and ghrelin O-acyl transferase (GOAT) genes. Peptides. 2011;32(11):2191-207..

Ghrelin and the genes

The human ghrelin gene (GHLR, Gene ID: 51738)7171 The National Center for Biotechnology Information [Internet]. Bethesda (MD): United State National Library of Medicine, c1992 – [cited 2015 Fev 11]. Available from: http://www.ncbi.nlm.nih.gov.
http://www.ncbi.nlm.nih.gov...
which encodes ghrelin is located in the short arm of the chromosome 3 (3p25-26)3333 Cowley MA, Smith RG, Diano S, Tschop M, Pronchuk N, Grove KL, et al. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron. 2003;37:649-61.. 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 humans7272 Seim I, Collet C, Herington AC, Chopin LK. Revised genomic structure of the human ghrelin gene and identification of novel exons, alternative splice variants and natural antisense transcripts. BMC Genomics. 2007;8:16.. 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 acids7373 Cellini E, Nacmias B, Brecelj-Anderluh D, Badia-Casanovas A, Bellodi L, Boni C, et al. Case–control and combined family trios analysis of three polymorphisms in the ghrelin gene in European patients with anorexia and bulimia nervosa. Psychiatr Genet. 2006;16:51-2., which include 23 of obestatin (a hormone with the antagonistic characteristics of ghrelin, which suppresses appetite and stomach activity)7474 Zhang JV, Ren PG, Avsian-Kretchmer O, Luo CW, Rauch R, Klein C, et al. Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin’s effects on food intake. Science. 2005;310:996-9.. Therefore, ghrelin and obestatin are encoded by the same precursor gene (Figure 2).

Figure 2
The human ghrelin gene (GHLR), also called the pre-proghrelin gene and its products. The upper boxes represent the exons, while the numbers at the bottom represent the amino acids. Adapted from Liu et al. 20117070 Liu B, Garcia EA, Korbonits M. Genetic studies on the ghrelin, growth hormone secretagogue receptor (GHSR) and ghrelin O-acyl transferase (GOAT) genes. Peptides. 2011;32(11):2191-207..

The gene of the receptor (GHS-R, Gene ID: 2693)7171 The National Center for Biotechnology Information [Internet]. Bethesda (MD): United State National Library of Medicine, c1992 – [cited 2015 Fev 11]. Available from: http://www.ncbi.nlm.nih.gov.
http://www.ncbi.nlm.nih.gov...
was also located in the chromosome 3 (3q-26-31)3131 Smith RG, Van der Ploeg LHT, Howard AD, Feighner SD, Cheng K, Hickey GJ, et al. Peptidomimetic regulation of growth hormone secretion. Endocr Rev. 1997;18:621-45.. 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 VII7575 McKee KK, Palyha OC, Feighner SD, Hreniuk DL, Tan CP, Phillips MS, et al. Molecular analysis of rat pituitary and hypothalamic growth hormone secretagogue receptors. Mol Endocrinol. 1997;11:415-23.. The GHS-R gene encodes two types of mRNA: GHS-R1a and GHS-R1b7373 Cellini E, Nacmias B, Brecelj-Anderluh D, Badia-Casanovas A, Bellodi L, Boni C, et al. Case–control and combined family trios analysis of three polymorphisms in the ghrelin gene in European patients with anorexia and bulimia nervosa. Psychiatr Genet. 2006;16:51-2.. 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 clear7676 Leung PK, Chow KBS, Lau PN, Chu KM, Chan CB, Cheng CHK, et al. The truncated ghrelin receptor polypeptide (GHS-R1b) acts as a dominant-negative mutant of the ghrelin receptor. Cell Signal. 2007;19:1011-22..

Figure 3
The growth hormone secretagogue receptor gene (GHS-R) and single nucleotide polymorphisms (SNPs) that are most researched in this gene, accompanied by their identification numbers. Adapted from Liu et al. 20117070 Liu B, Garcia EA, Korbonits M. Genetic studies on the ghrelin, growth hormone secretagogue receptor (GHSR) and ghrelin O-acyl transferase (GOAT) genes. Peptides. 2011;32(11):2191-207..

The gene of GOAT (MBOAT4; Gene ID: 619373)7171 The National Center for Biotechnology Information [Internet]. Bethesda (MD): United State National Library of Medicine, c1992 – [cited 2015 Fev 11]. Available from: http://www.ncbi.nlm.nih.gov.
http://www.ncbi.nlm.nih.gov...
is located in the chromosome 8 (8p12) and is expressed mainly in the stomach, in the pancreas and in lower concentrations in the bones7777 Gomez R, Lago F, Gomez-Reino JJ, Dieguez C, Gualillo O. Expression and modulation of ghrelin O-acyltransferase in cultured chondrocytes. Arthritis Rheum. 2009;60:1704-9.,7878 Gutierrez JA, Solenberg PJ, Perkins DR, Willency JA, Knierman MD, Jin Z, et al. Ghrelin octanoylation mediated by an orphan lipid transferase. Proc Natl Acad Sci USA. 2008;105:6320-5.. This gene represents a new candidate gene in genetic research for investigating complex phenotypes7070 Liu B, Garcia EA, Korbonits M. Genetic studies on the ghrelin, growth hormone secretagogue receptor (GHSR) and ghrelin O-acyl transferase (GOAT) genes. Peptides. 2011;32(11):2191-207. (Figure 4).

Figure 4
The enzyme ghrelin O-acyltransferase gene (GOAT) and single nucleotide polymorphisms (SNPs) that are most researched in this chromosome, accompanied by their identification numbers. Adapted from Liu et al. 20117070 Liu B, Garcia EA, Korbonits M. Genetic studies on the ghrelin, growth hormone secretagogue receptor (GHSR) and ghrelin O-acyl transferase (GOAT) genes. Peptides. 2011;32(11):2191-207..

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 diagnoses7373 Cellini E, Nacmias B, Brecelj-Anderluh D, Badia-Casanovas A, Bellodi L, Boni C, et al. Case–control and combined family trios analysis of three polymorphisms in the ghrelin gene in European patients with anorexia and bulimia nervosa. Psychiatr Genet. 2006;16:51-2.,8181 Ando T, Komaki G, Naruo T, Okabe K, Takii M, Kawai K, et al. Possible role of preproghrelin gene polymorphisms in susceptibility to bulimia nervosa. Am J Med Genet Part B-Neuropsychiatr Genet. 2006;B141:929-34.,8282 Monteleone P, Tortorella A, Castaldo E, Di Filippo C, Maj M. No association of the Arg51G1n and Leu72Met polymorphisms of the ghrelin gene with anorexia nervosa or bulimia nervosa. Neurosci Lett. 2006;398:325-7.,8484 Dardennes RM, Zizzari P, Tolle V, Foulon C, Kipman A, Romo L, et al. Family trios analysis of common polymorphisms in the obestatin/ghrelin, BDNF and AGRP genes in patients with Anorexia nervosa: Association with subtype, body-mass index, severity and age of onset. Psychoneuroendocrinology. 2007;32:106-13.,8686 Kindler J, Bailer U, de Zwaan M, Fuchs K, Leisch F, Grün B, et al. No association of the neuropeptide Y (Leu7Pro) and ghrelin gene (Arg51Gln, Leu72Met, Gln90Leu) single nucleotide polymorphisms with eating disorders. Nord J Psychiatry. 2011;65(3):203-7.. 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 EDs7979 Ando T. Ghrelin gene variants and eating disorders. Vitam Horm. 2013;92:107-23.. 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. 20068383 Miyasaka K, Hosoya H, Sekime A, Ohta M, Amono H, Matsushita S, et al. Association of ghrelin receptor gene polymorphism with bulimia nervosa in a Japanese population. J Neural Transm. 2006;113:1279-85. and Muller et al. 20108585 Muller TD, Tschop MH, Jarick I, Ehrlich S, Scherag S, Herpertz-Dahlmann B, et al. Genetic variation of the ghrelin activator gene ghrelin O-acyltransferase (GOAT) is associated with anorexia nervosa. J Psychiatr Res. 2011 May;45(5):706-11..

Conclusion

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.

Acknowledgments

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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Publication Dates

  • Publication in this collection
    Mar-Apr 2015

History

  • Received
    11 Feb 2015
  • Accepted
    4 Mar 2015
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