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Human Obesity Associated with an Intronic SNP in the Brain-Derived Neurotrophic Factor Locus
Zongyang Mou1, Thomas M Hyde2, Barbara K Lipska3
1Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA; Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA.
Cell Reports
|November 4, 2015
Summary
A specific gene variant (rs12291063 CC) is linked to lower brain-derived neurotrophic factor (BDNF) and increased obesity. This finding suggests BDNF therapy could target obesity in individuals with this genotype.
Area of Science:
- Neuroscience
- Genetics
- Metabolism
Background:
- Brain-derived neurotrophic factor (BDNF) is crucial for regulating energy balance.
- Single nucleotide polymorphisms (SNPs) in the BDNF gene are associated with obesity, but the underlying mechanisms remain unclear.
Purpose of the Study:
- To investigate the association between human hypothalamic BDNF expression and 44 BDNF SNPs.
- To elucidate the molecular mechanism linking BDNF genetic variants to obesity.
Main Methods:
- Analysis of human hypothalamic BDNF expression in relation to 44 BDNF SNPs.
- Genotyping and assessment of adiposity in adult and pediatric cohorts.
- Investigation of allele-specific transcriptional regulation involving heterogeneous nuclear ribonucleoprotein D0B (hnRNP-D0B).
Main Results:
- The minor C allele of rs12291063 was significantly associated with reduced hypothalamic BDNF expression (p < 0.001).
- Carriage of the rs12291063 C allele correlated with increased adiposity in both adult and pediatric populations (p < 0.05).
- The major T allele of rs12291063 binds hnRNP-D0B, a process essential for its transactivation; this binding and transactivation are impaired by the C allele.
Conclusions:
- The rs12291063 SNP influences hypothalamic BDNF expression and adiposity.
- Genetic variations in BDNF can mechanistically contribute to obesity development.
- Targeted BDNF augmentation may be a viable therapeutic strategy for obesity in individuals with the rs12291063 CC genotype.
Keywords:
Mou et al. show that brain-derived neurotrophic factor (BDNF) rs12291063 minor C allele disrupts binding and transactivation by the transcriptional regulatorand it is associated with lower ventromedial hypothalamic BDNF expression and obesity. BDNF augmentation may be specifically beneficial for treating obesity in individuals with the CC genotypeheterogeneous nuclear ribonucleoprotein D0BMore Related Videos
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