Cell Reports (Nov 2015)
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. Comuzzie,
- Michael 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
Affiliations
- Zongyang Mou
- Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA
- Thomas M. Hyde
- The Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Barbara K. Lipska
- Human Brain Collection Core, National Institute of Mental Health (NIMH), NIH, Bethesda, MD 20892, USA
- Keri Martinowich
- The Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Peter Wei
- Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA
- Chiew-Jen Ong
- Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA
- Lindsay A. Hunter
- Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA
- Gladys I. Palaguachi
- Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA
- Eva Morgun
- Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA
- Rujia Teng
- Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA
- Chen Lai
- Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA
- Tania A. Condarco
- Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA
- Andrew P. Demidowich
- Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA
- Amanda J. Krause
- Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA
- Leslie J. Marshall
- Preclinical Microbicide & Prevention Research Branch, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA
- Karin Haack
- Department of Genetics, Texas Biomedical Research Institute and Southwest National Primate Research Center, San Antonio, TX 78245, USA
- V. Saroja Voruganti
- Department of Genetics, Texas Biomedical Research Institute and Southwest National Primate Research Center, San Antonio, TX 78245, USA
- Shelley A. Cole
- Department of Genetics, Texas Biomedical Research Institute and Southwest National Primate Research Center, San Antonio, TX 78245, USA
- Nancy F. Butte
- USDA/ARS Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030, USA
- Anthony G. Comuzzie
- Department of Genetics, Texas Biomedical Research Institute and Southwest National Primate Research Center, San Antonio, TX 78245, USA
- Michael A. Nalls
- Molecular Genetics Section, National Institute of Aging (NIA), Bethesda, MD 20892, USA
- Alan B. Zonderman
- Behavioral Epidemiology Section, NIA, Baltimore, MD 21224, USA
- Andrew B. Singleton
- Molecular Genetics Section, National Institute of Aging (NIA), Bethesda, MD 20892, USA
- Michele K. Evans
- Health Disparities Research Section, NIA, Baltimore, MD 21224, USA
- Bronwen Martin
- Metabolism Unit, NIA, Baltimore, MD 21224, USA
- Stuart Maudsley
- Receptor Pharmacology Unit, NIA, Baltimore, MD 21224, USA
- Jack W. Tsao
- Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA
- Joel E. Kleinman
- The Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Jack A. Yanovski
- Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA
- Joan C. Han
- Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA
- DOI
- https://doi.org/10.1016/j.celrep.2015.09.065
- Journal volume & issue
-
Vol. 13,
no. 6
pp. 1073 – 1080
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.
Keywords
- 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
