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: 8.1). 01/2007; 55(12):3366-71. DOI: 10.2337/db06-0550
Source: PubMed


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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    • "Several lines of evidence suggest that Brain-derived neurotrophic factor (BDNF), a nerve growth factor which activates signaling by the tyrosine kinase receptor tropomycin-related kinase B (TrkB), and SIM1 may lie downstream of MC4R signaling in the paraventricular nucleus. Haploinsufficient mice and mice in which BDNF has been deleted postnatally are obese with hyperphagia and hyperactivity; this unusual combination of phenotypes is also seen in individuals with genetic disruption of BDNF or its receptor TrkB (Gray et al. 2006; Yeo et al. 2004). "
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    ABSTRACT: Body weight is a highly heritable trait across species. In humans, genetic variation plays a major role in determining the inter-individual differences in susceptibility or resistance to environmental factors which influence energy intake and expenditure. In this review, I discuss how genetic studies have contributed to our understanding of the central pathways that govern energy homeostasis. The study of individuals harboring highly penetrant genetic variants that disrupt the leptin-melanocortin pathway has informed our understanding of the physiological pathways involved in mammalian energy homeostasis.
    Mammalian Genome 08/2014; 25(9-10). DOI:10.1007/s00335-014-9541-z · 3.07 Impact Factor
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    • "In addition, reduced expression of BDNF was described in association with obesity in the leptin receptor deficient mouse [31], the Alzheimer disease mouse [32] and the Sf-1 KO mouse [3]. In humans, two reports show a relationship between BDNF (locus 11p14) and obesity [33], [34]. Patients with WAGR syndrome (Wilm’s tumor, aniridia, genitourinary anomalies and mental retardation, OMIM 194072) with a heterozygous 11p14 deletion including the BDNF gene suffer all from childhood onset obesity, while WAGR syndrome patients without genetic anomalies including the BDNF gene have normal prevalence of obesity [33]. "
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    ABSTRACT: Context: Human NR5A1/SF-1 mutations cause 46,XY disorder of sex development (DSD) with broad phenotypic variability, and rarely cause adrenal insufficiency although SF-1 is an important transcription factor for many genes involved in steroidogenesis. In addition, the Sf-1 knockout mouse develops obesity with age. Obesity might be mediated through Sf-1 regulating activity of brain-derived neurotrophic factor (BDNF), an important regulator of energy balance in the ventromedial hypothalamus. Objective: To characterize novel SF-1 gene variants in 4 families, clinical, genetic and functional studies were performed with respect to steroidogenesis and energy balance. Patients: 5 patients with 46,XY DSD were found to harbor NR5A1/SF-1 mutations including 2 novel variations. One patient harboring a novel mutation also suffered from adrenal insufficiency. Methods: SF-1 mutations were studied in cell systems (HEK293, JEG3) for impact on transcription of genes involved in steroidogenesis (CYP11A1, CYP17A1, HSD3B2) and in energy balance (BDNF). BDNF regulation by SF-1 was studied by promoter assays (JEG3). Results: Two novel NR5A1/SF-1 mutations (Glu7Stop, His408Profs*159) were confirmed. Glu7Stop is the 4th reported SF-1 mutation causing DSD and adrenal insufficiency. In vitro studies revealed that transcription of the BDNF gene is regulated by SF-1, and that mutant SF-1 decreased BDNF promoter activation (similar to steroid enzyme promoters). However, clinical data from 16 subjects carrying SF-1 mutations showed normal birth weight and BMI. Conclusions: Glu7Stop and His408Profs*159 are novel SF-1 mutations identified in patients with 46,XY DSD and adrenal insufficiency (Glu7Stop). In vitro, SF-1 mutations affect not only steroidogenesis but also transcription of BDNF which is involved in energy balance. However, in contrast to mice, consequences on weight were not found in humans with SF-1 mutations.
    PLoS ONE 08/2014; 9(8):e104838. DOI:10.1371/journal.pone.0104838 · 3.23 Impact Factor
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    • "Obesity has a strong genetic predisposition, with heritability estimates ranging from 65–80%.[7] Genome-wide association studies (GWAS) and candidate gene studies have identified many genetic loci influencing body weight or body fat distribution, most of them have important role in the central nervous system.[8]–[13] However, inter-individual variation in body weight or body fat distribution attributable to each single variant was marginal. "
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    ABSTRACT: Cigarette smoke is a strong risk factor for obesity and cardiovascular disease. The effect of genetic variants involved in nicotine metabolism on obesity or body composition has not been well studied. Though many genetic variants have previously been associated with adiposity or body fat distribution, a single variant usually confers a minimal individual risk. The goal of this study is to evaluate the joint association of multiple variants involved in cigarette smoke or nicotine dependence with obesity-related phenotypes in American Indians. To achieve this goal, we genotyped 61 tagSNPs in seven genes encoding nicotine acetylcholine receptors (nAChRs) in 3,665 American Indians participating in the Strong Heart Family Study. Single SNP association with obesity-related traits was tested using family-based association, adjusting for traditional risk factors including smoking. Joint association of all SNPs in the seven nAChRs genes were examined by gene-family analysis based on weighted truncated product method (TPM). Multiple testing was controlled by false discovery rate (FDR). Results demonstrate that multiple SNPs showed weak individual association with one or more measures of obesity, but none survived correction for multiple testing. However, gene-family analysis revealed significant associations with waist circumference (p = 0.0001) and waist-to-hip ratio (p = 0.0001), but not body mass index (p = 0.20) and percent body fat (p = 0.29), indicating that genetic variants are jointly associated with abdominal, but not general, obesity among American Indians. The observed combined genetic effect is independent of cigarette smoking per se. In conclusion, multiple variants in the nAChR gene family are jointly associated with abdominal obesity in American Indians, independent of general obesity and cigarette smoking per se.
    PLoS ONE 07/2014; 9(7):e102220. DOI:10.1371/journal.pone.0102220 · 3.23 Impact Factor
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