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Role of brain-derived neurotrophic factor in eating disorders: Recent findings and its pathophysiological implications

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Abstract

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. Recently, we 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.

Introduction

People suffering from eating disorders exhibit serious disturbances in eating behavior, such as extreme and unhealthy reduction of their food intake or severe overeating, as well as feelings of distress about, or extreme concern over, their body shape or weight. Eating disorders frequently develop during adolescence or early adulthood, but some studies have reported their onset during childhood or later in adulthood. Eating disorders affect some 1–3% of women in the United States (Becker et al., 1999, Kaye et al., 2000, Walsh and Devlin, 1998, Fairburn and Harrison, 2003, Klein and Walsh, 2004, Polivy and Herman, 2002). The major types of eating disorders are anorexia nervosa (AN) and bulimia nervosa (BN) that are diagnosed by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Ed. (DSM-IV; American Psychiatric Association; Table 1). The etiology of eating disorders is presumed to be complex, and to be influenced by multiple developmental, social, and biological processes (Becker et al., 1999, Kaye et al., 2000, Fairburn and Harrison, 2003, Walsh and Devlin, 1998, Klein and Walsh, 2004).

Brain-derived neurotrophic factor (BDNF) is recognized as a critical regulator in the survival, differentiation, and outgrowth of select peripheral and central neurons during development and in adulthood, and is also implicated in the synaptic plasticity of such brain functions as learning and memory (Snider, 1994, Thoenen, 2000, Schinder and Poo, 2000, Huang and Reichardt, 2001, Malcangio and Lessmann, 2003, Mattson, 2002, Mattson et al., 2003, Mattson et al., 2004, Lu, 2003a). Several lines of evidence suggest that BDNF plays an important role in the pathophysiology of psychiatric diseases, including mood disorders, and in the mechanism of action of therapeutic agents (Duman et al., 1997, Duman, 2002, Tamminga et al., 2002, Manji et al., 2003, Nestler et al., 2002, Coyle and Duman, 2003, Green and Craddock, 2003, Angelucci et al., 2004, Hashimoto et al., 2004).

Section snippets

Animal studies

There is also evidence supporting the critical role of BDNF in regulating eating behaviors in animals. For example, heterozygous BDNF (±) knock-out mice (e.g., approximately 50% levels of BDNF of wild-type mice) show enhanced inter-male aggressiveness and hyperphagia accompanied by significant weight gain in early adulthood, and these behavioral abnormalities have been correlated with 5-hydroxytryptamine (5-HT) dysfunction in the brain, since these behavioral abnormalities were ameliorated by

Human serum

Based on the role BDNF plays in eating behavior, it is important to assess the potential contribution of BDNF to the pathophysiology of eating disorders. Recently, we found that serum levels of BDNF in female patients with AN or BN were significantly decreased compared with those of age-matched normal control subjects, and we also found a significant positive correlation between the Bulimic Investigatory Test, Edinburgh (BITE) symptom scale (the severity of symptoms of bulimia), and the

Concluding remarks

It is well known that disturbances in neuronal systems have been found to play a role in the modulation of feeding, mood, and impulse control. These neuronal systems include neuropeptides [corticotropin-releasing hormone (CRH), opioids, neuropeptide-Y (NPY), peptide YY (PYY), vasopressin, oxytocin, cholecystokinin (CCK), leptin, and ghrelin] and monoamines (5-HT, dopamine, norepinephrine) (Barbarich et al., 2003). Recent studies with positron emission tomography (PET) demonstrated that altered

Acknowledgement

This study was supported by a Grant-in Aid for the Ministry of Health, Labor and Welfare of Japan (KH).

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