Human Obesity Associated with an Intronic SNP in the Brain-Derived Neurotrophic Factor Locus

Zongyang Mou, Thomas M. Hyde, Barbara K. Lipska, Keri Martinowich, Peter Wei, Chiew Jen Ong, Lindsay A. Hunter, Gladys I. Palaguachi, Eva Morgun, Rujia Teng, Chen Lai, Tania A. Condarco, Andrew P. Demidowich, Amanda J. Krause, Leslie J. Marshall, Karin Haack, V. Saroja Voruganti, Shelley A. Cole, Nancy F. Butte, Anthony G. ComuzzieMichael A. Nalls, Alan B. Zonderman, Andrew B. Singleton, Michele K. Evans, Bronwen Martin, Stuart Maudsley, Jack W. Tsao, Joel E. Kleinman, Jack A. Yanovski, Joan C. Han

Research output: Contribution to journalArticle

Abstract

Brain-derived neurotrophic factor (BDNF) plays a key role in energy balance. In population studies, SNPs of the BDNF locus have been linked to obesity, but the mechanism by which these variants cause weight gain is unknown. Here, we examined human hypothalamic BDNF expression in association with 44 BDNF SNPs. We observed that the minor C allele of rs12291063 is associated with lower human ventromedial hypothalamic BDNF expression (p < 0.001) and greater adiposity in both adult and pediatric cohorts (p values < 0.05). We further demonstrated that the major T allele for rs12291063 possesses a binding capacity for the transcriptional regulator, heterogeneous nuclear ribonucleoprotein D0B, knockdown of which disrupts transactivation by the T allele. Binding and transactivation functions are both disrupted by substituting C for T. These findings provide a rationale for BDNF augmentation as a targeted treatment for obesity in individuals who have the rs12291063 CC genotype. Mou et al. show that brain-derived neurotrophic factor (BDNF) rs12291063 minor C allele disrupts binding and transactivation by the transcriptional regulator, heterogeneous nuclear ribonucleoprotein D0B, and 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 genotype.

Original languageEnglish (US)
Pages (from-to)1073-1080
Number of pages8
JournalCell Reports
Volume13
Issue number6
DOIs
StatePublished - Nov 10 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Mou, Z., Hyde, T. M., Lipska, B. K., Martinowich, K., Wei, P., Ong, C. J., Hunter, L. A., Palaguachi, G. I., Morgun, E., Teng, R., Lai, C., Condarco, T. A., Demidowich, A. P., Krause, A. J., Marshall, L. J., Haack, K., Voruganti, V. S., Cole, S. A., Butte, N. F., ... Han, J. C. (2015). Human Obesity Associated with an Intronic SNP in the Brain-Derived Neurotrophic Factor Locus. Cell Reports, 13(6), 1073-1080. https://doi.org/10.1016/j.celrep.2015.09.065