Role for the brain-derived neurotrophic factor (BDNF) in eating disorder, anorexia nervosa (AN) and bulimia nervosa (BN)

Several lines of evidence indicate a role of the brain-derived neurotrophic factor (BDNF) in the modulation of eating behaviour. Therefore, alterations in the physiology of this neurotrophin may be involved in the pathogenesis of eating disorders. Eating disorders (ED), such as anorexia nervosa (AN) and bulimia nervosa (BN), are complex psychiatric disorders where different genetic and environmental factors are involved. In the present study, we investigated serum levels of BDNF in patients with anorexia nervosa (AN), bulimia nervosa (BN) and binge-eating disorder (BED).

Eating disorders, which include anorexia nervosa (AN) and bulimia nervosa (BN), are disorders characterized by abnormal patterns of weight regulation and eating behaviors, and by disturbances in attitudes and perceptions toward weight and body shape. Brain-derived neurotrophic factor (BDNF) plays a critical role in regulating neural survival, development, function, and plasticity in the brain. Recent findings using heterozygous BDNF (+/-) knock-out (reduced BDNF levels) mice have provided evidence that BDNF plays a role in regulating eating behaviors.

Some study found that serum levels of BDNF in patients with eating disorders are significantly decreased compared with normal controls. In addition, an association between the BDNF gene polymorphism and eating disorders has been demonstrated. We reviewed the role of BDNF in the pathophysiology of eating disorders and the BDNF gene as a susceptibility gene for eating disorders. Considering the low levels of BDNF in patients with eating disorders, using drugs that increase the BDNF levels and/or BDNF gene therapy are possible novel therapeutic approaches. Providing confirmation that the BDNF gene is the true susceptibility gene for eating disorders could lead to rapid therapeutic progress in treating these disorders. In addition, a more complete understanding of the signal transduction pathway via the p75 neurotrophin receptor (p75NTR) and TrkB receptors would provide new perspectives for treating eating disorders.

Several lines of evidence suggest that brain-derived neurotrophic factor (BDNF) plays an important role in weight regulation and eating behavior, and poorly balanced diets lead to a decrease in blood BDNF levels. However, studies regarding BDNF blood levels in eating disorders (ED) have yielded inconsistent results.

Murine models and association studies in eating disorder (ED) patients have shown a role for the brain-derived neurotrophic factor (BDNF) in eating behavior. Some studies have shown association of BDNF -270C/T single-nucleotide polymorphism (SNP) with bulimia nervosa (BN), while BDNF Val66Met variant has been shown to be associated with both BN and anorexia nervosa (AN).

Several lines of evidence support that brain-derived neurotrophic factor (BDNF) plays an essential role in eating behaviour and that alterations on this neurotrophic system participates in the susceptibility to both AN and BN. Accordingly, intraventricular administration of BDNF in rats determines food starvation and body weight loss, while BDNF or its specific receptor NTRK2 knockout mice develop obesity and hyperphagia. Case-control studies also suggest a BDNF contribution in the aetiology of ED Ribases have previously reported a strong association between the Met66 variant within the BDNF gene, restricting AN (ANR) and minimum body mass index (minBMI) in a Spanish sample, and a positive association between the Val66Met and -270C/T BDNF SNPs and ED in six different European populations. To replicate these results, avoiding population stratification effects, Ribases recruited 453 ED trios from eight European centres and performed a family-based association study. Both haplotype relative risk (HRR) and haplotype-based haplotype relative risk (HHRR) methods showed a positive association between the Met66 allele and ANR. He observed an effect of the Met66 variant on low minBMI and a preferential transmission of the -270C/Met66 haplotype to the affected ANR offspring. These results support the involvement of BDNF in eating behaviour and further suggest its participation in the genetic susceptibility to ED, mainly ANR and low minBMI.

Saito reported that individuals showing more extreme food intake regulation were those with lower serum BDNF levels. This finding is contrary to that in mice where mice with reduced BDNF levels showed aberrant eating behavior. This result suggests that BDNF is no longer functioning appropriately in ED patients, which could be an important factor in the pathophysiological of ED.

Monteleone findings evidentiate alterations in serum BDNF levels in malnourished patients with AN or BN, but not in well-nourished individuals with BED. Since BDNF seems to exert a satiety effect, its reduction may represent an adaptive change to counteract the decreased calorie ingestion of AN and BN individuals.

Role for the brain-derived neurotrophic factor (BDNF) in eating behavior shown association of BDNF -270C/T single-nucleotide polymorphism (SNP) with bulimia nervosa (BN), while BDNF Val66Met variant has been shown to be associated with both BN and anorexia nervosa (AN). To further test the role of this neurotrophin in humans, we screened 36 SNPs in the BDNF gene and tested for their association with ED and plasma BDNF levels as a quantitative trait.

Mercaerder performed a family-based association study in 106 ED nuclear families and analyzed BDNF blood levels in 110 ED patients and in 50 sib pairs discordant for ED. The rs7124442T/rs11030102C/rs11030119G haplotype was found associated with high BDNF levels (mean BDNF TCG haplotype carriers = 43.6 ng/ml vs. mean others 23.0 ng/ml, P = 0.016) and BN (Z = 2.64; P recessive = 0.008), and the rs7934165A/270T haplotype was associated with AN (Z =-2.64; P additive = 0.008). The comparison of BDNF levels in 50 ED discordant sib pairs showed elevated plasma BDNF levels for the ED group (mean controls = 41.0 vs. mean ED = 52.7; P = 0.004). Our data strongly suggest that altered BDNF levels modulated by BDNF gene variability are associated with the susceptibility to ED, providing physiological evidence that BDNF plays a role in the development of AN and BN, and strongly arguing for its involvement in eating behavior and body weight regulation.

References

1. Nakazato M, et al. Possible involvement of brain-derived neurotrophic factor in eating disorders. IUBMB Life. 2012 Apr 4.

2. Hashimoto K, et al. Role of brain-derived neurotrophic factor in eating disorders: recent findings and its pathophysiological implications. Prog Neuropsychopharmacol Biol Psychiatry. 2005 May;29(4):499-504.

3. Ribasés M, et al. Met66 in the brain-derived neurotrophic factor (BDNF) precursor is associated with anorexia nervosa restrictive type. Mol Psychiatry. 2003 Aug;8(8):745-51.

4. Saito S, et al. Low serum BDNF and food intake regulation: a possible new explanation of the pathophysiology of eating disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2009 Mar 17;33(2):312-6.

5. Monteleone P, et al.Circulating brain-derived neurotrophic factor is decreased in women with anorexia and bulimia nervosa but not in women with binge-eating disorder: relationships to co-morbid depression, psychopathology and hormonal variables. Psychol Med. 2005 Jun;35(6):897-905.

7. Mercader JM, et al. Altered brain-derived neurotrophic factor blood levels and gene variability are associated with anorexia and bulimia. Genes Brain Behav. 2007 Nov;6(8):706-16.

8. Ribasés M, et al. Association of BDNF with restricting anorexia nervosa and minimum body mass index: a family-based association study of eight European populations. Eur J Hum Genet. 2005 Apr;13(4):428-34.

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