PMID- 26526993 OWN - NLM STAT- MEDLINE DCOM- 20160824 LR - 20210109 IS - 2211-1247 (Electronic) VI - 13 IP - 6 DP - 2015 Nov 10 TI - Human Obesity Associated with an Intronic SNP in the Brain-Derived Neurotrophic Factor Locus. PG - 1073-1080 LID - S2211-1247(15)01107-9 [pii] LID - 10.1016/j.celrep.2015.09.065 [doi] AB - 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. CI - Copyright (c) 2015 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Mou, Zongyang AU - Mou Z AD - 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. FAU - Hyde, Thomas M AU - Hyde TM AD - 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. FAU - Lipska, Barbara K AU - Lipska BK AD - Human Brain Collection Core, National Institute of Mental Health (NIMH), NIH, Bethesda, MD 20892, USA. FAU - Martinowich, Keri AU - Martinowich K AD - 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. FAU - Wei, Peter AU - Wei P AD - 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. FAU - Ong, Chiew-Jen AU - Ong CJ AD - 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. FAU - Hunter, Lindsay A AU - Hunter LA AD - 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. FAU - Palaguachi, Gladys I AU - Palaguachi GI AD - 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. FAU - Morgun, Eva AU - Morgun E AD - 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. FAU - Teng, Rujia AU - Teng R AD - Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA. FAU - Lai, Chen AU - Lai C AD - 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. FAU - Condarco, Tania A AU - Condarco TA AD - Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA. FAU - Demidowich, Andrew P AU - Demidowich AP AD - Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA. FAU - Krause, Amanda J AU - Krause AJ AD - Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA. FAU - Marshall, Leslie J AU - Marshall LJ AD - Preclinical Microbicide & Prevention Research Branch, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA. FAU - Haack, Karin AU - Haack K AD - Department of Genetics, Texas Biomedical Research Institute and Southwest National Primate Research Center, San Antonio, TX 78245, USA. FAU - Voruganti, V Saroja AU - Voruganti VS AD - 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. FAU - Cole, Shelley A AU - Cole SA AD - Department of Genetics, Texas Biomedical Research Institute and Southwest National Primate Research Center, San Antonio, TX 78245, USA. FAU - Butte, Nancy F AU - Butte NF AD - USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030, USA. FAU - Comuzzie, Anthony G AU - Comuzzie AG AD - Department of Genetics, Texas Biomedical Research Institute and Southwest National Primate Research Center, San Antonio, TX 78245, USA. FAU - Nalls, Michael A AU - Nalls MA AD - Molecular Genetics Section, National Institute of Aging (NIA), Bethesda, MD 20892, USA. FAU - Zonderman, Alan B AU - Zonderman AB AD - Behavioral Epidemiology Section, NIA, Baltimore, MD 21224, USA. FAU - Singleton, Andrew B AU - Singleton AB AD - Molecular Genetics Section, National Institute of Aging (NIA), Bethesda, MD 20892, USA. FAU - Evans, Michele K AU - Evans MK AD - Health Disparities Research Section, NIA, Baltimore, MD 21224, USA. FAU - Martin, Bronwen AU - Martin B AD - Metabolism Unit, NIA, Baltimore, MD 21224, USA. FAU - Maudsley, Stuart AU - Maudsley S AD - 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. FAU - Tsao, Jack W AU - Tsao JW AD - 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. FAU - Kleinman, Joel E AU - Kleinman JE AD - 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. FAU - Yanovski, Jack A AU - Yanovski JA AD - Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA. FAU - Han, Joan C AU - Han JC AD - 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. LA - eng GR - U01 HG004802/HG/NHGRI NIH HHS/United States GR - L60 MD001417/MD/NIMHD NIH HHS/United States GR - U01HG004803/HG/NHGRI NIH HHS/United States GR - Z99 HD999999/ImNIH/Intramural NIH HHS/United States GR - ZIA HD000641-20/ImNIH/Intramural NIH HHS/United States GR - U01 HG004803/HG/NHGRI NIH HHS/United States GR - U01HG004798/HG/NHGRI NIH HHS/United States GR - ZIA MH002399-23/ImNIH/Intramural NIH HHS/United States GR - Z99 CL999999/ImNIH/Intramural NIH HHS/United States GR - U01HG004801/HG/NHGRI NIH HHS/United States GR - R01 DK080457/DK/NIDDK NIH HHS/United States GR - U01HG004790/HG/NHGRI NIH HHS/United States GR - U01 HG004798/HG/NHGRI NIH HHS/United States GR - R01 DK59264/DK/NIDDK NIH HHS/United States GR - R01 DK059264/DK/NIDDK NIH HHS/United States GR - Z99 MH999999/ImNIH/Intramural NIH HHS/United States GR - U01 HG004790/HG/NHGRI NIH HHS/United States GR - ZIA AG000513-15/ImNIH/Intramural NIH HHS/United States GR - U01HG004802/HG/NHGRI NIH HHS/United States GR - ZIA HD008898-05/ImNIH/Intramural NIH HHS/United States GR - ZIC MH002903-06/ImNIH/Intramural NIH HHS/United States GR - U01 HG004801/HG/NHGRI NIH HHS/United States GR - ZIA HD008898-01/ImNIH/Intramural NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, N.I.H., Intramural DEP - 20151029 PL - United States TA - Cell Rep JT - Cell reports JID - 101573691 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (HNRNPD protein, human) RN - 0 (Heterogeneous Nuclear Ribonucleoprotein D0) RN - 0 (Heterogeneous-Nuclear Ribonucleoprotein D) RN - 7171WSG8A2 (BDNF protein, human) SB - IM MH - Adolescent MH - Adult MH - Brain-Derived Neurotrophic Factor/*genetics/metabolism MH - Case-Control Studies MH - Child MH - Female MH - HEK293 Cells MH - Heterogeneous Nuclear Ribonucleoprotein D0 MH - Heterogeneous-Nuclear Ribonucleoprotein D/metabolism MH - Humans MH - Hypothalamus/metabolism MH - Introns MH - Male MH - Middle Aged MH - Obesity/*genetics MH - *Polymorphism, Single Nucleotide MH - Protein Binding PMC - PMC4644471 MID - NIHMS726075 OTO - NOTNLM OT - Mou et al. show that brain-derived neurotrophic factor (BDNF) rs12291063 minor C allele disrupts binding and transactivation by the transcriptional regulator OT - 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 OT - heterogeneous nuclear ribonucleoprotein D0B EDAT- 2015/11/04 06:00 MHDA- 2016/08/25 06:00 PMCR- 2015/11/14 CRDT- 2015/11/04 06:00 PHST- 2014/09/24 00:00 [received] PHST- 2015/08/27 00:00 [revised] PHST- 2015/09/23 00:00 [accepted] PHST- 2015/11/04 06:00 [entrez] PHST- 2015/11/04 06:00 [pubmed] PHST- 2016/08/25 06:00 [medline] PHST- 2015/11/14 00:00 [pmc-release] AID - S2211-1247(15)01107-9 [pii] AID - 10.1016/j.celrep.2015.09.065 [doi] PST - ppublish SO - Cell Rep. 2015 Nov 10;13(6):1073-1080. doi: 10.1016/j.celrep.2015.09.065. Epub 2015 Oct 29.