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

doi:10.1016/j.celrep.2015.09.065

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

Cell Rep. 2015 Nov 10;13(6):1073-1080. doi: 10.1016/j.celrep.2015.09.065. Epub 2015 Oct 29.

Authors

Zongyang Mou¹, Thomas M Hyde², Barbara K Lipska³, Keri Martinowich⁴, Peter Wei⁵, Chiew-Jen Ong⁵, Lindsay A Hunter⁵, Gladys I Palaguachi⁵, Eva Morgun¹, Rujia Teng⁶, Chen Lai⁵, Tania A Condarco⁷, Andrew P Demidowich⁷, Amanda J Krause⁷, Leslie J Marshall⁸, Karin Haack⁹, V Saroja Voruganti¹⁰, Shelley A Cole⁹, Nancy F Butte¹¹, Anthony G Comuzzie⁹, Michael A Nalls¹², Alan B Zonderman¹³, Andrew B Singleton¹², Michele K Evans¹⁴, Bronwen Martin¹⁵, Stuart Maudsley¹⁶, Jack W Tsao¹⁷, Joel E Kleinman², Jack A Yanovski⁷, Joan C Han¹⁸

Affiliations

¹ Unit 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.
² The Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ Human Brain Collection Core, National Institute of Mental Health (NIMH), NIH, Bethesda, MD 20892, USA.
⁴ The Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁵ Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA; Departments of Neurology and Physical Medicine and Rehabilitation, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
⁶ Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA.
⁷ Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA.
⁸ Preclinical Microbicide & Prevention Research Branch, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
⁹ Department of Genetics, Texas Biomedical Research Institute and Southwest National Primate Research Center, San Antonio, TX 78245, USA.
¹⁰ Department of Genetics, Texas Biomedical Research Institute and Southwest National Primate Research Center, San Antonio, TX 78245, USA; Department of Nutrition and UNC Nutrition Research Institute, University of North Carolina, Chapel Hill, Kannapolis, NC 28081, USA.
¹¹ USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030, USA.
¹² Molecular Genetics Section, National Institute of Aging (NIA), Bethesda, MD 20892, USA.
¹³ Behavioral Epidemiology Section, NIA, Baltimore, MD 21224, USA.
¹⁴ Health Disparities Research Section, NIA, Baltimore, MD 21224, USA.
¹⁵ Metabolism Unit, NIA, Baltimore, MD 21224, USA.
¹⁶ Receptor Pharmacology Unit, NIA, Baltimore, MD 21224, USA; Translational Neurobiology Group, VIB Department of Molecular Genetics, University of Antwerp, 2610 Wilrijk, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, 2610 Wilrijk, Belgium.
¹⁷ Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA; Departments of Neurology and Physical Medicine and Rehabilitation, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA; Department of Neurology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
¹⁸ Unit 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; Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38163, USA; Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, TN 38103, USA. Electronic address: jhan14@uthsc.edu.

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; 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; heterogeneous nuclear ribonucleoprotein D0B.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural

MeSH terms

Adolescent
Adult
Brain-Derived Neurotrophic Factor / genetics*
Brain-Derived Neurotrophic Factor / metabolism
Case-Control Studies
Child
Female
HEK293 Cells
Heterogeneous Nuclear Ribonucleoprotein D0
Heterogeneous-Nuclear Ribonucleoprotein D / metabolism
Humans
Hypothalamus / metabolism
Introns
Male
Middle Aged
Obesity / genetics*
Polymorphism, Single Nucleotide*
Protein Binding

Substances

Brain-Derived Neurotrophic Factor
HNRNPD protein, human
Heterogeneous Nuclear Ribonucleoprotein D0
Heterogeneous-Nuclear Ribonucleoprotein D
BDNF protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding