@article{d53ca44f8e044ac2a0ee901759bdf7c1,
title = "Human Obesity Associated with an Intronic SNP in the Brain-Derived Neurotrophic Factor Locus",
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.",
author = "Zongyang Mou and Hyde, {Thomas M.} and Lipska, {Barbara K.} and Keri Martinowich and Peter Wei and Ong, {Chiew Jen} and Hunter, {Lindsay A.} and Palaguachi, {Gladys I.} and Eva Morgun and Rujia Teng and Chen Lai and Condarco, {Tania A.} and Demidowich, {Andrew P.} and Krause, {Amanda J.} and Marshall, {Leslie J.} and Karin Haack and Voruganti, {V. Saroja} and Cole, {Shelley A.} and Butte, {Nancy F.} and Comuzzie, {Anthony G.} and Nalls, {Michael A.} and Zonderman, {Alan B.} and Singleton, {Andrew B.} and Evans, {Michele K.} and Bronwen Martin and Stuart Maudsley and Tsao, {Jack W.} and Kleinman, {Joel E.} and Yanovski, {Jack A.} and Han, {Joan C.}",
note = "Funding Information: This research was supported by the Intramural Research Program of NICHD and NIMH with supplemental funding from the NIH Bench to Bedside Program to J.C.H. and the National Institute of Minority Health and Health Disparities to J.A.Y. The Viva la Familia studies were supported by the NIH (R01 DK59264 and R01 DK080457 to N.F.B.). A.J.K. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the NIH Division of Nutrition Research Coordination. The PAGE program is funded by National Human Genome Research Institute (NHGRI), supported by U01HG004803 (CALiCo), U01HG004798 (EAGLE), U01HG004802 (MEC), U01HG004790 (WHI), and U01HG004801 (Coordinating Center), and their respective NHGRI American Recovery and Reinvestment Act (ARRA) supplements. We thank Ms. Amy Deep-Soboslay and Drs. Lewellyn B. Bigelow and Mary M. Herman for their contributions in assembling the postmortem human brain cohorts for study, Dr. Amanda Preston for editorial assistance, and the families of the decedents for their generous donation of tissue. J.A.Y. is a Commissioned Officer of the United States Public Health Service. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Public Health Service, Department of the Navy, Department of Defense, or Department of Health and Human Services. Publisher Copyright: {\textcopyright} 2015 The Authors.",
year = "2015",
month = nov,
day = "10",
doi = "10.1016/j.celrep.2015.09.065",
language = "English (US)",
volume = "13",
pages = "1073--1080",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "6",
}