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Keywords:

  • brain-derived neurotrophic factor;
  • eating disorders;
  • anorexia nervosa;
  • bulimia nervosa;
  • recovery;
  • biological marker

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BDNF AND EATING BEHAVIORS
  5. ANIMAL STUDIES
  6. HUMAN SERUM AND PLASMA BDNF
  7. GENETIC STUDIES
  8. DECREASED LEVELS OF SERUM BDNF IN INDIVIDUALS WITH EDS
  9. BDNF IN RECOVERED AN
  10. COMORBID MENTAL DISORDERS AND SERUM BDNF
  11. BDNF AND COGNITIVE FLEXIBILITY IN EDS
  12. ASSOCIATION OF SERUM BDNF LEVEL AND MALNUTRITION
  13. CONCLUDING REMARKS
  14. Acknowledgements
  15. REFERENCES

Eating disorders (EDs) manifest as abnormal patterns of eating behavior and weight regulation driven by low self-esteem due to weight preoccupation and perceptions toward body weight and shape. Two major groups of such disorders are anorexia nervosa (AN) and bulimia nervosa (BN). The etiology of EDs is complex and evidence indicates that both biological/genetic and psychosocial factors are involved. Several lines of evidence indicate that brain-derived neurotrophic factor (BDNF) plays a critical role in regulating eating behaviors and cognitive impairments in the EDs. BDNF is involved in neuronal proliferation, differentiation, and survival during development. BDNF and its tyrosine kinase receptor (TrkB) are expressed in hypothalamic nuclei associated with eating behaviors. A series of studies using BDNF knockout mice and the human BDNF gene indicate an association of BDNF and EDs with predisposition and vulnerability. In the previous studies, serum BDNF levels in subjects with EDs are reduced significantly compared with healthy controls, hence, we proposed that levels of serum BDNF would be a useful diagnostic indicator for EDs. © 2012 IUBMB IUBMB Life, 2012


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BDNF AND EATING BEHAVIORS
  5. ANIMAL STUDIES
  6. HUMAN SERUM AND PLASMA BDNF
  7. GENETIC STUDIES
  8. DECREASED LEVELS OF SERUM BDNF IN INDIVIDUALS WITH EDS
  9. BDNF IN RECOVERED AN
  10. COMORBID MENTAL DISORDERS AND SERUM BDNF
  11. BDNF AND COGNITIVE FLEXIBILITY IN EDS
  12. ASSOCIATION OF SERUM BDNF LEVEL AND MALNUTRITION
  13. CONCLUDING REMARKS
  14. Acknowledgements
  15. REFERENCES

Brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor family, which includes nerve growth factor, neurotrophin-3, and neurotrophin-4/5 (1–3). BDNF binds to a specific receptor TrkB, which is present on the surface of target cells, and regulates the growth of neuronal cells by mediating processes such as survival, development, and enhanced synaptic activity. Besides neuronal growth, differentiation, maintenance, and potentiation, BDNF also modulates neurotransmitters, such as dopamine, and neural plasticity and binding mechanisms underlying long-term potentiation and learning/memory (1–4). BDNF is widely distributed in the central nervous system (CNS), beginning early in development and extending throughout in the life span. In human brain, BDNF is most abundant in several regions, including the hippocampus and the cerebral cortex (1–3). BDNF readily crosses the blood–brain barrier in both directions, and therefore, a substantial part of circulating BDNF concentrations may originate from neurons and glia cells in the CNS. In the peripheral tissues, it is acquired from plasma membrane, partly produced in vascular endothelial cells or smooth muscle cells, then internalized and stored mainly in the platelets, and later, it is released into plasma through activation or clotting process (5).

The average serum levels of BDNF were about between 50- and 100-fold higher than plasma levels; the difference is due to degranulation of platelets during the clotting process. BNDF is initially synthesized as a precursor protein proBDNF, and then proBDNF is proteolytically cleaved to the mature BDNF. The BDNF gene produced precursor proteinBDNF (preproBDNF) in the endoplasmic reticulum. ProBDNF binds to intracellular sortilin in the Golgi to facilitate proper folding of the mature domain. ProBDNF preferentially binds p75NTR receptors. ProBDNF is cleaved by proteases at the synapses and concertedto mature BDNF. Mature BDNF preferentially binds tropomyosin receptor kinase (Trk) B receptor (ref. 6; Fig. 1). BDNF and TrkB are expressed in various hypothalamic nuclei associated with eating behavior. In animal studies, mice heterozygous for the BDNF gene (reduced BDNF levels) develop enhanced intermale aggressiveness and hyperphagia accompanied by significant weight gain in early adulthood, and these behavioral abnormalities are known to correlate with serotonergic dysfunction (6). BDNF gene of heterozygous knockout mice demonstrates increased levels of stress anxiety, locomotor activity, and abnormalities in eating behavior (7, 8).

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Figure 1. The synthesis of BDNF from proBDNF. This figure is referred from the article by Hashimoto (6).

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Eating disorders (EDs) manifest as abnormal patterns of eating behavior and weight regulation driven by low self-esteem due to weight preoccupation and perceptions toward body weight and shape. Two major groups of such disorders are anorexia nervosa (AN) and bulimia nervosa (BN). Anorexic problems mainly involve low body weight, fear toward weight gain, persistent restriction of food intake, and pursuit of regulating weight and shape. BN is characterized by repetitive cycle of excessive uncontrolled binge eating followed by compensatory behavior such as purging. AN and BN are frequently observed among young women, the typical onset in adolescence to adulthood. In Europe and North America, the combined prevalence of AN (9, 10) among young women is reported to be 0.1–0.5% and that of BN (11) is 1.5–3.8%. They have been a major focus of attention for both the research community and sometimes life-threatening group of problems, predominantly affecting women.

The pathophysiology of EDs has been studied from various aspects, and a range of factors including biological and psychosocial factors are linked to the onset and persistence of symptoms. Some studies showed risk factors for EDs such as low self-esteem, anxiety, harm avoidance, impulsive control and obsessive–compulsive personality traits, and cognitive inflexibility (12); however, the details of biological markers for the pathophysiology of EDs are unknown. Identification of the biological markers of EDs is crucial for the development of new treatments as well as to aid both in the diagnosis and management. In addition, they could provide the basis for early intervention and prevention efforts targeting at-risk individuals.

Recently, there has been a series of findings on the involvement of BDNF in the pathophysiology of EDs (11). According to genetic studies on BDNF and EDs (13, 14), and a meta-analysis of the BDNF gene, a 30% higher incidence of EDs is seen among individuals with the Val/Met and the Met/Met polymorphism of the BDNF gene (13), indicating that the BDNF Val66Met (rs6265) polymorphism is linked to EDs. On the other hand, an association of the BDNF gene with other mental disorders, such as mood disorders and substance abuse disorders, have also been reported (14, 15). Thus, the special relevance of the BDNF gene to EDs is currently unclear.

In Japanese subjects, we previously revealed the associations of the BDNF Val66Met polymorphism with AN (restricting type) and BN (purging type) (16). In the previous studies, serum BDNF levels in subjects with EDs are reduced significantly when compared with healthy controls (HCs), and hence, we proposed that levels of serum BDNF would be a useful diagnostic indicator for EDs (17–19). Here, we introduce a number of studies on serum BDNF and EDs, describe the associations between BDNF and the pathophysiological features of EDs, and propose challenges and new perspectives for the future research.

BDNF AND EATING BEHAVIORS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BDNF AND EATING BEHAVIORS
  5. ANIMAL STUDIES
  6. HUMAN SERUM AND PLASMA BDNF
  7. GENETIC STUDIES
  8. DECREASED LEVELS OF SERUM BDNF IN INDIVIDUALS WITH EDS
  9. BDNF IN RECOVERED AN
  10. COMORBID MENTAL DISORDERS AND SERUM BDNF
  11. BDNF AND COGNITIVE FLEXIBILITY IN EDS
  12. ASSOCIATION OF SERUM BDNF LEVEL AND MALNUTRITION
  13. CONCLUDING REMARKS
  14. Acknowledgements
  15. REFERENCES

BDNF is the most abundant neurotrophic factor in the brain and is a member of the nerve growth factor family that includes nerve growth factor, neurotrophin-3, and neurotrophin-4/5 (1–3). BDNF also modulates networks of neurotransmitters, such as dopaminergic (20, 21), serotoninergic (22), and glutamatergic neurotransmission (23), and plays a role in neural plasticity and binding mechanisms underlying long-term potentiation and learning/memory (1).

BDNF binds to a specific tyrosine kinase receptor, TrkB. BDNF is a 27-kDa polypeptide, which easily crosses through the blood–brain barrier (24, 25). BDNF functions as a neurotrophic factor and plays a role in the modulation and integration of signaling pathways in the nervous, immune, and endocrine systems (26). It also influences regulatory mechanisms of weight (27), eating behavior (27), and metabolism.

The human BDNF gene is located on chromosome 11p13 and comprises 11 exons. The gene encodes a precursor protein proBDNF (6), which mediates secretion and cellular transportation of BDNF. Synthesis of preproBDNF and its conversion to a single proBDNF peptide take place in the lumen of the endoplasmic reticulum, followed by transportation to the Golgi apparatus. ProBDNF preferentially binds p75NTR receptors. ProBDNF is cleaved by proteases at the synapses and is converted to mature BDNF, and it participates in a range of important physiological activities (6). Originally, proBDNF was considered biologically inactive; however, recent evidence shows them to be important factors that can bind to neurotrophin receptors and induce effects opposite to the mature BDNF (22, 28, 29).

ANIMAL STUDIES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BDNF AND EATING BEHAVIORS
  5. ANIMAL STUDIES
  6. HUMAN SERUM AND PLASMA BDNF
  7. GENETIC STUDIES
  8. DECREASED LEVELS OF SERUM BDNF IN INDIVIDUALS WITH EDS
  9. BDNF IN RECOVERED AN
  10. COMORBID MENTAL DISORDERS AND SERUM BDNF
  11. BDNF AND COGNITIVE FLEXIBILITY IN EDS
  12. ASSOCIATION OF SERUM BDNF LEVEL AND MALNUTRITION
  13. CONCLUDING REMARKS
  14. Acknowledgements
  15. REFERENCES

Among BDNF transgenic mice, BDNF+/− knockout mice exhibit hyperactivity, high anxiety, and weight gain under stress (8, 30). BDNF+/− knockout mice also show aggressiveness and excessive appetite in early adulthood (7). BDNF−/− homozygote mutant mice die within a few weeks after birth (31, 32). In animal studies, appetite increases when the expression of TrkB in the hypothalamus is low, and BDNF regulates energy balance through melanocortin-4 receptor in the hypothalamus (33). Another study showed that dietary restriction (DR) may alter the behaviors in BDNF+/− mice and that the 5-HT system may be implicated in the beneficial effects of DR on these behaviors (34). Such findings indicate that the BDNF gene product is involved in the modulation of anxiety, eating behavior, and weight control.

HUMAN SERUM AND PLASMA BDNF

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BDNF AND EATING BEHAVIORS
  5. ANIMAL STUDIES
  6. HUMAN SERUM AND PLASMA BDNF
  7. GENETIC STUDIES
  8. DECREASED LEVELS OF SERUM BDNF IN INDIVIDUALS WITH EDS
  9. BDNF IN RECOVERED AN
  10. COMORBID MENTAL DISORDERS AND SERUM BDNF
  11. BDNF AND COGNITIVE FLEXIBILITY IN EDS
  12. ASSOCIATION OF SERUM BDNF LEVEL AND MALNUTRITION
  13. CONCLUDING REMARKS
  14. Acknowledgements
  15. REFERENCES

BDNF is widely distributed in the CNS (33) and is especially abundant in the hippocampus, prefrontal cortex, ventral tegmental area, and amygdala. High levels of BDNF and TrkB are found in the hypothalamus, which is one of the major regulatory centers for eating behavior (30). BDNF in the CNS crosses through the blood–brain barrier (24, 25). In the periphery, it is synthesized mainly in vascular endothelial cells and smooth muscle cells (35) and is stored in platelets (5). BDNF also circulates in plasma due to granulation of coagulation factors. In humans, the levels of plasma BDNF decrease with age, and in women, the levels of serum BDNF vary according to the phase of menstrual cycles (27).

When compared with serum BDNF, plasma BDNF is sensitive to environmental factors (35). Animal studies have shown a correlation between serum BDNF levels in the cortex and those in the hippocampus (24, 36). In rats, BDNF levels in serum and brain are highly correlated across all age groups (37).

GENETIC STUDIES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BDNF AND EATING BEHAVIORS
  5. ANIMAL STUDIES
  6. HUMAN SERUM AND PLASMA BDNF
  7. GENETIC STUDIES
  8. DECREASED LEVELS OF SERUM BDNF IN INDIVIDUALS WITH EDS
  9. BDNF IN RECOVERED AN
  10. COMORBID MENTAL DISORDERS AND SERUM BDNF
  11. BDNF AND COGNITIVE FLEXIBILITY IN EDS
  12. ASSOCIATION OF SERUM BDNF LEVEL AND MALNUTRITION
  13. CONCLUDING REMARKS
  14. Acknowledgements
  15. REFERENCES

The frequency of the BDNF196G/A (Val66Met) polymorphism is higher among Japanese than Europeans and North Americans (37). The number of patients with EDs carrying the BDNF196G/A allele, especially of the AN restricting or BN purging type, is significantly high when compared with that of the HCs (16). Correlations were also observed between the energy intake and the body mass index (BMI) (38), AN restricting type, and minimum BMI value (38, 39). With regard to cognitive dysfunction and when compared with BDNF Val/Val allele carriers, individuals with the BDNF Val/Met allele demonstrate frontal lobe cognitive dysfunction (40), whereas those with the BDNF Met66 allele show episodic memory dysfunction (41, 42).

DECREASED LEVELS OF SERUM BDNF IN INDIVIDUALS WITH EDS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BDNF AND EATING BEHAVIORS
  5. ANIMAL STUDIES
  6. HUMAN SERUM AND PLASMA BDNF
  7. GENETIC STUDIES
  8. DECREASED LEVELS OF SERUM BDNF IN INDIVIDUALS WITH EDS
  9. BDNF IN RECOVERED AN
  10. COMORBID MENTAL DISORDERS AND SERUM BDNF
  11. BDNF AND COGNITIVE FLEXIBILITY IN EDS
  12. ASSOCIATION OF SERUM BDNF LEVEL AND MALNUTRITION
  13. CONCLUDING REMARKS
  14. Acknowledgements
  15. REFERENCES

We hypothesized that serum BDNF levels would be a candidate biological markers in patients with EDs for both abnormal eating behavior and cognitive impairment related to body shape and weight. Accordingly, we compared serum BDNF levels of female patients with AN and BN with those of HCs. BDNF levels among patients with AN and BN were significantly reduced when compared with those of HCs (P < 0.0001). Furthermore, the BDNF levels were significantly lower in the patients with AN than in the patients with BN. In all subjects, there was a significant correlation between serum BDNF levels and BMI (17).

Following our study, other groups also reported reduced levels of serum BDNF in patients with EDs (43–46). In the two previous studies, serum BDNF levels (45) and BMI (46) were positively correlated with AN. In all the subjects, including subjects with AN and HC, the correlation between serum BDNF level and BMI has been established (17, 18, 43, 44). Although the present findings suggest correlations between BMI, one of the severity indexes of AN, and serum BDNF, a meta-analysis of circulating BDNF in AN (47) confirmed significant heterogeneity of effect size (Table 1).

Table 1. Data from studies measuring serum BDNF levels in patients with AN and healthy controls
AuthorEthnicityNumber of EDsNumber of HCsAN ageHC ageAN BMIHC BMIAN BDNF (ng/mL) (+/−)HC BDNF (ng/mL) (+/−)
  1. Abbreviations: AN, anorexia nervosa; HC, healthy controls; BDNF, brain-derived neurotrophic factor.

Nakazato et al. (17)Japanese12 AN2119.6 (5.8)20.4 (2)14.2 (0.7)20.4 (2)24.9 (6.75)61.4 (19.5)
Monteleone et al. (43)Italian12 AN2720.5 (5.4)22.3 (3.4)15.6 (1.8)22 (1.9)26.65 (12.46)45.8 (29.1)
Monteleone et al. (44)Italian27 AN2420 (5.2)22.4 (3.4)15.9 (2.4)21.8 (1.8)28.87 (16.36)50 (27.92)
Nakazato et al. (18)Japanese13 AN1719.6 (5.8)20.4 (2)14.2 (0.7)20.4 (1.5)14.5 (4.4)22.1 (8.9)
Saito et al. (45)Japanese19 AN2425.3 (7.9)24.5 (5.7)14.0 (2.1)20.4 (2.4)20.0 (5.1)26.0 (3.9)
Nakazato et al. (19)British29 AN2828.3 (11)26.9 (5.8)15.6 (1.6)22.3 (2.5)11.7 (4.9)15.1 (5.5)
Ehrlich et al. (46)German33 AN3318.9 (3.9)19 (3.1)14.9 (1.4)21.4 (2.1)6.16 (2.88)7.41 (3.22)

Another group invested the correlation of the Eating Disorders Inventory (EDI) scales with BDNF plasma levels and suggested that BDNF levels of both of the AN and BN may influence the severity of EDs by modulating the associated psychopathology, in particular through the impairment of interoceptive awareness (48). Regarding hypothalamic-pituitary-adrenal (HPA) axis reactivity and BDNF polymorphism, BDNF Val(66)Met carriers are particularly sensitive in anticipating stressful events in healthy adults (49).

BDNF IN RECOVERED AN

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BDNF AND EATING BEHAVIORS
  5. ANIMAL STUDIES
  6. HUMAN SERUM AND PLASMA BDNF
  7. GENETIC STUDIES
  8. DECREASED LEVELS OF SERUM BDNF IN INDIVIDUALS WITH EDS
  9. BDNF IN RECOVERED AN
  10. COMORBID MENTAL DISORDERS AND SERUM BDNF
  11. BDNF AND COGNITIVE FLEXIBILITY IN EDS
  12. ASSOCIATION OF SERUM BDNF LEVEL AND MALNUTRITION
  13. CONCLUDING REMARKS
  14. Acknowledgements
  15. REFERENCES

In the previous pilot study, we longitudinally compared serum BDNF levels of patients with AN before and after partial recovery of their BMI (18). We did not observe a statistically significant difference. However, in the cross-sectional study, serum BDNF levels of AN group were significantly lower than those of not only the HCs but also the recovered AN group which had 1) a history of AN, 2) maintained BMI levels ranging from 18.5 to 25 kg/m2 for at least 1 year, and 3) maintained a regular menstrual cycle for at least 1 year (19).

Ehrlich et al. (46) compared serum BDNF levels between 33 patients with AN, seven subjects in partial recovery after a longitudinal follow-up (>10% weight gain), 20 patients with AN in the recovery phase, and 33 HCs. The results showed that, when compared with current AN, serum BDNF levels in the partial recovery group were slightly higher; however, the difference between the two groups was not statistically significant. Although BDNF levels in the recovered AN group were increased when compared with those in the current AN and HC groups, again the differences did not attain statistical significance.

COMORBID MENTAL DISORDERS AND SERUM BDNF

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BDNF AND EATING BEHAVIORS
  5. ANIMAL STUDIES
  6. HUMAN SERUM AND PLASMA BDNF
  7. GENETIC STUDIES
  8. DECREASED LEVELS OF SERUM BDNF IN INDIVIDUALS WITH EDS
  9. BDNF IN RECOVERED AN
  10. COMORBID MENTAL DISORDERS AND SERUM BDNF
  11. BDNF AND COGNITIVE FLEXIBILITY IN EDS
  12. ASSOCIATION OF SERUM BDNF LEVEL AND MALNUTRITION
  13. CONCLUDING REMARKS
  14. Acknowledgements
  15. REFERENCES

EDs are often associated with mental disorders such as mood disorders and anxiety disorders. A high prevalence of concurrent mood disorders has been observed among patients with AN, and the involvement of genetic and environmental factors has been reported (50). Reduced levels of BDNF were found in the postmortem brains of individuals who suffered from depression (51). Studies using an animal model of depression have reported reduced BDNF levels in the CNS and the recovery of BDNF mRNA levels in the hippocampus after administration of antidepressants (52, 53). In individuals with depression, decreased levels of serum BDNF have been demonstrated (50). A meta-analysis also revealed that reduced serum BDNF levels are associated with depression, whereas antidepressant administration reverses such reduction of serum BDNF levels (54, 55). Recent study showed that classification based on the DNA methylation profiles of CpG I of the BDNF gene may be a valuable diagnostic biomarker for major depression (56). Obsessive–compulsive disorders often comorbid with AN (57), and serum BDNF levels in individuals with obsessive–compulsive disorders are also reduced when compared with HCs (58).

In our previous study (17), the Hamilton Depression Rating Scale (HDRS) of the participants with EDs was significantly lower than that of HCs. A significant positive correlation between HDRS and the Bulimic Investigatory Test, Edinburgh (BITE) symptom scale scores in all the patients was detected. Some lines of evidence suggest that altered 5-HT activity in patients with EDs could be a consequence of pathologic EDs. Furthermore, in the pharmacological treatment of EDs, antidepressants, including Selective Serotonin Reuptake Inhibitors (SSRI), have been shown to decrease symptoms of binge eating and purging behaviors, in addition to depressive symptoms. The 5-HT systems in the brain have been strongly associated with BDNF regulation of food intake, demonstrating that endogenous BDNF is critical for the normal development and functioning of central 5-HT neurons (7).

The differences were shown between AN and depression that pharmacotherapy with antidepressants results in normalization of BDNF levels in depressed patients and contributes to recovery or alleviation of symptoms, and on the other hand, little or no efficacy in AN treatment.

BDNF AND COGNITIVE FLEXIBILITY IN EDS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BDNF AND EATING BEHAVIORS
  5. ANIMAL STUDIES
  6. HUMAN SERUM AND PLASMA BDNF
  7. GENETIC STUDIES
  8. DECREASED LEVELS OF SERUM BDNF IN INDIVIDUALS WITH EDS
  9. BDNF IN RECOVERED AN
  10. COMORBID MENTAL DISORDERS AND SERUM BDNF
  11. BDNF AND COGNITIVE FLEXIBILITY IN EDS
  12. ASSOCIATION OF SERUM BDNF LEVEL AND MALNUTRITION
  13. CONCLUDING REMARKS
  14. Acknowledgements
  15. REFERENCES

To study the relationship between BDNF and cognitive flexibility, we performed the Wisconsin Card Sorting Test as a set-shifting task. The results showed that patients with AN had a higher number of both incorrect answers and perseverative errors than HCs. However, there was no obvious correlation between serum BDNF levels and set-shifting dysfunction (17).

ASSOCIATION OF SERUM BDNF LEVEL AND MALNUTRITION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BDNF AND EATING BEHAVIORS
  5. ANIMAL STUDIES
  6. HUMAN SERUM AND PLASMA BDNF
  7. GENETIC STUDIES
  8. DECREASED LEVELS OF SERUM BDNF IN INDIVIDUALS WITH EDS
  9. BDNF IN RECOVERED AN
  10. COMORBID MENTAL DISORDERS AND SERUM BDNF
  11. BDNF AND COGNITIVE FLEXIBILITY IN EDS
  12. ASSOCIATION OF SERUM BDNF LEVEL AND MALNUTRITION
  13. CONCLUDING REMARKS
  14. Acknowledgements
  15. REFERENCES

A connection between anorexia–cachexia syndrome and cytokines has also been suggested (59). Anorexia–cachexia syndrome associated with malignant tumor, chronic renal failure, cardiovascular disease, and chronic rheumatoid arthritis is marked by a reduction in muscle mass and fat tissue, and a series of changes in the metabolic, immune, and endocrine systems. Inflammatory cytokines in the circulation, such as tumor necrosis factor and interleukin-6, are elevated, while growth factors like BDNF are also affected by the syndrome. Peripheral cytokines are known to modulate neurotransmitter and neuropeptide functions through the hypothalamus (59). In AN, calorie deficit, severe malnutrition, reduced muscle mass and fat tissue, and stress-related biological responses are believed to cause a series of changes to peripheral cytokines. However, further study is needed to elucidate the mechanisms of such changes.

CONCLUDING REMARKS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BDNF AND EATING BEHAVIORS
  5. ANIMAL STUDIES
  6. HUMAN SERUM AND PLASMA BDNF
  7. GENETIC STUDIES
  8. DECREASED LEVELS OF SERUM BDNF IN INDIVIDUALS WITH EDS
  9. BDNF IN RECOVERED AN
  10. COMORBID MENTAL DISORDERS AND SERUM BDNF
  11. BDNF AND COGNITIVE FLEXIBILITY IN EDS
  12. ASSOCIATION OF SERUM BDNF LEVEL AND MALNUTRITION
  13. CONCLUDING REMARKS
  14. Acknowledgements
  15. REFERENCES

ED, especially AN, is a severe mental illness for which an appropriate treatment has yet to be established. Various factors have been proposed as the link between the pathophysiology of EDs and the reduced level of serum BDNF.

A series of studies using BDNF knockout mice and the human BDNF gene indicate an association of BDNF and EDs with predisposition and vulnerability. Changes in brain BDNF were observed in a mouse model of depression and in mice suffering early maternal separation (60), in which stress and environmental factors during early developmental stages were suggested as causative factors. Epigenetic factors based on the DNA methylation of the BDNF gene might be a valuable biomarker for EDs, as well as depression (61, 62).

A variety of factors including influence of concurrent mental disorders and peripheral responses to starvation have also been considered. In addition, there is a question whether serum BDNF is a state marker or trait marker (Fig. 2).

thumbnail image

Figure 2. The hypothesis for etiology of eating disorders affected by BDNF. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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Further studies regarding BDNF and proBDNF are needed to elucidate the pathophysiology of EDs and to develop candidate biomarkers and their treatments. It is also important to perform animal studies of EDs to investigate changes in eating behaviors and anxiety disorders following BDNF administration. We would look forward to an innovative research field with high potential for developing treatments for EDs and discovering new drugs that work through BDNF and other nerve growth factors.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BDNF AND EATING BEHAVIORS
  5. ANIMAL STUDIES
  6. HUMAN SERUM AND PLASMA BDNF
  7. GENETIC STUDIES
  8. DECREASED LEVELS OF SERUM BDNF IN INDIVIDUALS WITH EDS
  9. BDNF IN RECOVERED AN
  10. COMORBID MENTAL DISORDERS AND SERUM BDNF
  11. BDNF AND COGNITIVE FLEXIBILITY IN EDS
  12. ASSOCIATION OF SERUM BDNF LEVEL AND MALNUTRITION
  13. CONCLUDING REMARKS
  14. Acknowledgements
  15. REFERENCES
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