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Hyperphagia, Severe Obesity, Impaired Cognitive Function, and Hyperactivity Associated With Functional Loss of One Copy of the Brain-Derived Neurotrophic Factor (BDNF) Gene

Department of Biochemistry, University of Cambridge, Cambridge, England, United Kingdom
Diabetes (Impact Factor: 8.47). 01/2007; 55(12):3366-71. DOI: 10.2337/db06-0550
Source: PubMed

ABSTRACT The neurotrophin brain-derived neurotrophic factor (BDNF) inhibits food intake, and rodent models of BDNF disruption all exhibit increased food intake and obesity, as well as hyperactivity. We report an 8-year-old girl with hyperphagia and severe obesity, impaired cognitive function, and hyperactivity who harbored a de novo chromosomal inversion, 46,XX,inv(11)(p13p15.3), a region encompassing the BDNF gene. We have identified the proximal inversion breakpoint that lies 850 kb telomeric of the 5' end of the BDNF gene. The patient's genomic DNA was heterozygous for a common coding polymorphism in BDNF, but monoallelic expression was seen in peripheral lymphocytes. Serum concentration of BDNF protein was reduced compared with age- and BMI-matched subjects. Haploinsufficiency for BDNF was associated with increased ad libitum food intake, severe early-onset obesity, hyperactivity, and cognitive impairment. These findings provide direct evidence for the role of the neurotrophin BDNF in human energy homeostasis, as well as in cognitive function, memory, and behavior.

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Available from: Anna-Lynne R Adlam, Jul 29, 2015
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    • "Indeed, several reports have demonstrated that the serum levels of BDNF were low in obese adults and children and in subjects with metabolic syndrome (MS) 7—10. Among subgroup with WAGR syndrome, those with BDNF haploinsufficiency have low levels of serum BDNF and become hyperphagic and develop childonset obesity [11] [12]. Additionally, recent studies also revealed that single-nucleotide polymorphisms (SNPs) in BDNF genes are strongly related with BMI and childhood obesity [13] [14]. "
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    ABSTRACT: Background Brain-derived neurotrophic factor (BDNF) plays important roles in the central regulation of food intake and body weight control. However, little is known about the role of BDNF in childhood obesity. Objective To investigate the relationship between plasma levels of BDNF and anthropometric factors, metabolic derangements due to obesity, adipocytokine levels and birth weight in obese Japanese children. Subjects and methods Sixty-six obese Japanese children aged from 5 to 15 years old were enrolled. The age-matched control group consisted of 32 non-obese healthy children. The plasma levels of BDNF and adipocytokines (leptin and adiponectin) were assayed using ELISA techniques. Results The mean BMI Z-scores were −0.67, +2.15 and +3.39 for the non-obese control children, obese (BMI ≥ 90th percentile, <99th percentile) and morbidly obese (BMI ≥ 99th percentile), respectively. The plasma levels of BDNF were significantly decreased in the morbidly obese children compared with the levels in the obese and non-obese control children (507 ± 33 pg/ml vs. 626 ± 46 pg/ml, 621 ± 35 pg/ml, p < 0.05). Univariate linear regression analysis showed that the plasma level of BDNF was positively correlated with birth weight (r = 0.264, p < 0.05) and inversely correlated with the BMI Z-score (r = −0.314, p < 0.05). Multivariate forward stepwise linear regression analysis revealed that the birth weight and BMI Z-score are independent predictors of the plasma BDNF level. Conclusion The plasma level of BDNF, which is decreased in morbidly obese children, is associated with birth weight and the BMI Z-score. Our results suggest that BDNF may play important roles in the development and pathophysiology of childhood obesity.
    Obesity Research & Clinical Practice 02/2014; 8(1):e63–e69. DOI:10.1016/j.orcp.2012.07.003 · 0.70 Impact Factor
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    • "Markedly increased food consumption and extreme obesity were also found in TrkB hypomorphic mice in which TrkB expression was reduced to a quarter of the normal amount [14]. In humans, BDNF haploinsufficiency, due to the loss of a functional Bdnf copy [15] or deletion of one Bdnf locus in patients with Wilms tumor, aniridia, genitourinary anomalies, and mental retardation syndrome [16], is associated with decreased serum BDNF concentrations, hyperphagia, and obesity. A pilot study also links insufficient central BDNF production to the Prader–Willi syndrome [17]. "
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    ABSTRACT: Brain-derived neurotrophic factor (BDNF) and its cognate receptor, TrkB (tropomyosin receptor kinase B), are widely expressed in the brain where they regulate a wide variety of biological processes, including energy homeostasis. However, the specific population(s) of TrkB-expressing neurons through which BDNF governs energy homeostasis remain(s) to be determined. Using the Cre-loxP recombination system, we deleted the mouse TrkB gene in RGS9-2-expressing cells. In this mouse mutant, TrkB expression was abolished in several hypothalamic nuclei, including arcuate nucleus, dorsomedial hypothalamus, and lateral hypothalamus. TrkB expression was also abolished in a small number of cells in other brain regions, including the cerebral cortex and striatum. The mutant animals developed hyperphagic obesity with normal energy expenditure. Despite hyperglycemia under fed conditions, these animals exhibited normal fasting blood glucose levels and normal glucose tolerance. These results suggest that BDNF regulates energy homeostasis in part through TrkB-expressing neurons in the hypothalamus.
    11/2013; 2(4):491-497. DOI:10.1016/j.molmet.2013.08.002
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    • "One case report described obesity and cognitive impairment in a child with a paracentric 11p13p15.3 inversion and functional BDNF haploinsufficiency (Gray et al., 2006). Two case series described a total of 9 subjects with 11p14 deletions involving BDNF who displayed obesity and various neurodevelopmental abnormalities, including intellectual disability, attention deficit hyperactivity disorder, and autism (Ernst et al., 2012; Shinawi et al., 2011). "
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    ABSTRACT: In animal studies, brain-derived neurotrophic factor (BDNF) is an important regulator of central nervous system development and synaptic plasticity. WAGR (Wilms tumour, Aniridia, Genitourinary anomalies, and mental Retardation) syndrome is caused by 11p13 deletions of variable size near the BDNF locus and can serve as a model for studying human BDNF haploinsufficiency (+/-). We hypothesized that BDNF+/- would be associated with more severe cognitive impairment in subjects with WAGR syndrome. Twenty-eight subjects with WAGR syndrome (6-28 years), 12 subjects with isolated aniridia due to PAX6 mutations/microdeletions (7-54 years), and 20 healthy controls (4-32 years) received neurocognitive assessments. Deletion boundaries for the subjects in the WAGR group were determined by high-resolution oligonucleotide array comparative genomic hybridization. Within the WAGR group, BDNF+/- subjects (n = 15), compared with BDNF intact (+/+) subjects (n = 13), had lower adaptive behaviour (p = .02), reduced cognitive functioning (p = .04), higher levels of reported historical (p = .02) and current (p = .02) social impairment, and higher percentage meeting cut-off score for autism (p = .047) on Autism Diagnostic Interview-Revised. These differences remained nominally significant after adjusting for visual acuity. Using diagnostic measures and clinical judgement, 3 subjects (2 BDNF+/- and 1 BDNF+/+) in the WAGR group (10.7%) were classified with autism spectrum disorder. A comparison group of visually impaired subjects with isolated aniridia had cognitive functioning comparable to that of healthy controls. In summary, among subjects with WAGR syndrome, BDNF+/- subjects had a mean Vineland Adaptive Behaviour Compose score that was 14-points lower and a mean intelligence quotient (IQ) that was 20-points lower than BDNF+/+ subjects. Our findings support the hypothesis that BDNF plays an important role in human neurocognitive development.
    Cortex 02/2013; 49(10). DOI:10.1016/j.cortex.2013.02.009 · 6.04 Impact Factor
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