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From the Department of Psychiatry, Institution University of Naples SUN, Naples, Italy.
Address correspondence and reprint requests to Palmiero Monteleone, MD, Department of Psychiatry, Institution University of Naples SUN, Largo Madonna delle Grazie, 80138 Naples, Italy. E-mail: monteri{at}tin.it
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: We measured morning serum levels of BDNF in 22 women with AN, 24 women with obesity (body mass index [BMI] > 30 kg/m2), and 27 nonobese healthy women. All the subjects were drug-free and underwent a clinical assessment by means of rating scales measuring both eating-related psychopathology and depressive symptoms.
RESULTS: As compared with the nonobese healthy controls, circulating BDNF was significantly reduced in AN patients and significantly increased in obese subjects. No significant difference was observed in serum BDNF concentrations between AN women with or without a comorbid depressive disorder. Moreover, serum BDNF levels were significantly and positively correlated with the subjects’ body weight and BMI.
CONCLUSION: The BDNF changes observed in AN and obesity are likely secondary adaptive mechanisms aimed at counteracting the change in energy balance that occurs in these syndromes.
Key Words: anorexia nervosa, • brain-derived neurotrophic factor, • obesity, • eating behavior, • body mass index.
Abbreviations: AN = anorexia nervosa;; BW = body weight;; BDNF = brain-derived neurotrophic factor;; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th Edition;; SCID-I = Structured Clinical Interview for DSM-IV Axis 1 Disorders;; BMI = body mass index;; MINI = Mini International Neuropsychiatric Interview;; EDI = Eating Disorder Inventory;; BITE = Bulimic Investigation Test Edinburgh;; MADRS = Montgomery-Asberg Depression Rating Scale;; ANOVA = analysis of variance;; 5-HT = serotonin.
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INTRODUCTION |
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The brain-derived neurotrophic factor (BDNF) is the most abundant of neurotrophins in the brain and the periphery that promote neuronal outgrowth and differentiation, synaptic connectivity, and neuronal repair (1,2). Recently, a role of this neurotrophin in the modulation of eating behavior has been demonstrated. In particular, it has been shown that heterozygous mice with one functional BDNF allele and mice in which the BDNF gene has been deleted in excitatory brain neurons display obesity phenotypes with increased locomotor activity (3–5). Moreover, both central and peripheral administration of BDNF decrease food intake, increase energy expenditure, and ameliorate hyperinsulinaemia and hyperglicaemia in diabetic db/db mice by a central nervous system-mediated mechanism (6–9). In addition, BDNF and its tyrosine kinase receptor are expressed in various hypothalamic nuclei implicated in the regulation of eating behavior (4). Collectively, these findings suggest that BDNF signaling in the brain may play a major role in regulating energy homeostasis and BW, although the precise mechanisms through which it exerts these effects are still poorly understood. Therefore, alterations in BDNF function or expression pattern could be considered susceptibility factors to disordered eating.
Recently, decreased levels of serum BDNF have been found in a relatively small sample of underweight women with AN (10). To the best of our knowledge, no study has assessed circulating levels of this neurotrophin in people with obesity. Therefore, studies aiming to explore BDNF physiology in people with these disorders are warranted.
In our study, we measured serum concentrations of BDNF in both drug-free underweight women with AN and women with obesity, and compared them with those of normal-weight sex-matched healthy controls.
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METHODS |
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According to the obesity criteria of both the World Health Organization (12) and the International Obesity Task Force (13), 24 patients suffered from obesity (body mass index [BMI] > 30 kg/m2) without binge-eating behavior. All endocrine diseases known to cause obesity were excluded. No pharmacological or dietetic treatment was introduced before our investigation. They had never taken psychotropic drugs.
Nonobese drug-free control women (BMI < 25.0) were recruited among medical students and clinical staff. They were mentally healthy, as assessed by the Mini International Neuropsychiatric Interview (MINI) (14), and had regular menses and normal diets. Clinical interviews were performed by an experienced psychiatrist trained in the use of several psychiatric interviews.
Both patients and healthy volunteers had normal values of routine blood and urine tests and a normal electrocardiogram, and they were free from nonpsychotropic medications from at least 8 weeks. None of them was taking oral contraceptives or had a past history of alcohol or drug abuse, as ascertained by the SCID-I in patients and by the MINI in nonobese controls.
Female controls and patients who were normally menstruating were tested in the follicular phase of their menstrual cycle (day 5–10 from menses).
Procedures
Subjects gave written informed consent before study participation. Patients underwent the following clinical assessments: (1) comorbid axis I psychiatric disorders were investigated by using the SCID-I; (2) psychopathological aspects were rated by means of the Eating Disorder Inventory-2 (EDI-2) (15) and the Bulimia Investigation Test Edinburgh (BITE) (16), which evaluated eating-related psychopathology, and by the Montgomery-Asberg Depression Rating Scale (MADRS) (17), which measured depressive symptoms.
In each subject, BW and height were measured, and the BMI was calculated. All subjects underwent blood sample collection in the morning between 08:00 and 09:00 hours, after an overnight fast. Blood was withdrawn by venipuncture and collected in tubes that were allowed to clot at room temperature. Serum was separated by centrifugation and stored at –80°C until assayed.
Biochemical Analyses
Serum BDNF levels were determined by an enzyme-linked immunosorbent assay method with the BDNF Emax Immunoassay System kit (Promega, Madison, WI), according to the manufacturer’s instructions. The lower detection limit was 7.8 pg/ml. Intra- and interassay coefficients of variation were 2.9% and <9%, respectively.
Statistical Analysis
The Biomedical Computer Program statistical software package (18) was used for data analysis. Data distributions were examined for normality and homogeneity of variance. Because there were significant deviations from normality in BDNF data, nonparametric statistical analyses were used. Where the Kruskal-Wallis analysis of variance (ANOVA) showed significant differences among the groups, the Mann-Whitney U test was used to assess differences in the two group comparisons. According to Bonferroni’s correction for multiple comparisons, the significance level was set at p = .016. The Spearman rank order correlation test was used to examine the relationship between BDNF values and nutritional or clinical variables.
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RESULTS |
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Biochemical Data
Kruskal-Wallis ANOVA showed significant intergroup differences in serum levels of BDNF (H = 28.126, p < .0001). Compared with healthy women, AN patients had significantly reduced values of serum BDNF (p = .013), whereas obese women had significantly enhanced levels of the neurotrophin (p < .001; Figure 1). Mean (±SD) serum BDNF levels did not significantly differ between AN patients with comorbid major depression and those without such a comorbidity (30.1 ± 11.9 ng/ml vs. 25.0 ± 12.8 ng/ml) or between anorexics of the restricted subtype (25.3 ± 13.3 ng/ml) and those of the binge-purging subtype (29.0 ± 11.3 ng/ml).
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= 0.61, p < .0001) and BMI ( = 0.57, p < .0001) in all subjects, whereas no significant correlations between these parameters were found in each diagnostic group. Moreover, no significant correlations emerged between serum levels of the neurotrophin, on the one hand, and age, BITE total and subitem scores, EDI-2 subitem scores, duration of the illness, and MADRS total scores, on the other hand, in all patients and in each diagnostic group. |
DISCUSSION |
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Consistent with our findings, Nakazato et al. (10) reported that, in a small group of women with AN, serum BDNF levels were significantly decreased and did not significantly correlate with the severity of concomitant depressive symptoms assessed by the Hamilton Depression Rating Scale. However, in that study, AN patients were not screened for comorbid depressive disorders. In our opinion, this is a crucial point, because accumulating evidence suggests BDNF as a candidate molecule involved in the pathophysiology of mood disorders. In particular, decreased levels of BDNF have been detected in the serum of both drug-naive and antidepressant-free patients with major depression (19,20), whereas an increased expression of the neurotrophin has been reported in the hippocampus of subjects treated with antidepressant medications at the time of the death (21). Finally, impaired BDNF expression and its increase after chronic antidepressant drug or electroconvulsive treatments have been reported in animal models of depression (22–25). Because mood disorders frequently co-occur with AN (26), the possibility exists that reduced levels of serum BDNF in AN patients are related to the co-occurrence of a mood disorder and an eating disorder. Our results indicate for the first time that reduced BDNF concentrations in people with AN are not related to the presence of comorbid major depression, because serum concentrations of BDNF did not significantly differ between AN patients with or without a comorbid depressive disorder, and they were not correlated to the severity of depressive symptomatology. However, because of the small number of subjects, these data should be regarded as preliminary.
Because impairments of BDNF production in the experimental animal have been associated with increased food intake, reduced energy expenditure, and weight gain (3–8), if one hypothesizes a pathogenetic role for this neurotrophin in human obesity and AN, decreased BDNF levels in obesity and enhanced concentrations in AN would be expected. Instead, we found increased concentrations of serum BDNF in obese individuals and decreased levels of the neurotrophin in AN subjects. This suggests that changes in circulating BDNF in AN and obesity are likely secondary to the altered energy balance occurring in these syndromes. One hypothesis could be that in AN, BDNF reduction, by promoting food intake, attempts to counterbalance the patients’ altered behaviors that lead to a negative energy balance. On the contrary, in obesity, increased levels of BDNF may represent an adaptive mechanism to counteract the condition of positive energy imbalance by stimulating energy expenditure and decreasing food ingestion. This hypothesis is corroborated by the finding that, in our whole subject sample, serum BDNF concentrations were significantly and positively correlated with the subjects’ BW and BMI. The mechanism through which BDNF would exert these effects is likely to involve serotonin (5-HT) transmission, which is known to play a major role in the modulation of eating behavior by acting as a satiety factor (27). Indeed, pharmacological studies indicate that exogenously administered BDNF has trophic effects on 5-HT neurons by stimulating the local sprouting of serotonergic fibers in the cerebral cortex and spinal cord (28,29). Furthermore, it has been shown that BDNF-deficient mice develop physiological disturbances in central 5-HT neurons in early adulthood that are associated with exaggerated aggressiveness and excessive food intake (30).
Although the origin of serum BDNF still remains unknown, platelets have been shown to be able to bind, store, and release BDNF on activation in a manner similar to that of 5-HT (31). Therefore, one further explanation of BDNF changes observed in patients with AN or obesity may be represented by modifications in either the release of the neurotrophin from platelets and/or alterations in the platelet number. Studies aiming to assess specifically the platelet number and the BDNF release from platelets of both AN and obese people are needed to clarify this issue. Furthermore, thrombocytopenia has been shown to occur in nearly one third of AN patients (32); hence, the possibility exists that, at least in AN, a reduced platelet number could account for the decrease in serum BDNF.
One limitation of this study is that we measured circulating BDNF; therefore, the question arises whether peripheral BDNF reflects neurotrophin levels in the brain. It has been demonstrated in the rat that brain and serum BDNF concentrations undergo parallel changes during maturation and aging (33); furthermore, BDNF has been shown to be able to cross the blood–brain barrier (34). All these data support the view that peripheral BDNF changes reflect similar changes in the brain, where its modulatory role on eating behavior is likely to be exerted (6–8). A second shortcoming is that in order to have subjects matched for sex, we were obliged to include only female obese individuals. Therefore, our results do not necessarily extend to obese men. Finally, the marked age difference between the obese group and the other two groups could have theoretically confounded the results; however, the absence of significant correlation between age and serum BDNF levels is reassuring on this point.
In conclusion, we have shown that circulating BDNF is decreased in drug-free women with AN and increased in those with obesity. These BDNF changes are likely secondary to the alterations of energy balance that occur in these syndromes, and they may represent adaptive mechanisms that aim to counteract changes in eating behavior and energy expenditure.
Received for publication February 27, 2004.
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