Mou Zongyang, Hyde Thomas M, Lipska Barbara K, Martinowich Keri, Wei Peter, Ong Chiew-Jen, Hunter Lindsay A, Palaguachi Gladys I, Morgun Eva, Teng Rujia, Lai Chen, Condarco Tania A, Demidowich Andrew P, Krause Amanda J, Marshall Leslie J, Haack Karin, Voruganti V Saroja, Cole Shelley A, Butte Nancy F, Comuzzie Anthony G, Nalls Michael A, Zonderman Alan B, Singleton Andrew B, Evans Michele K, Martin Bronwen, Maudsley Stuart, Tsao Jack W, Kleinman Joel E, Yanovski Jack A, Han Joan C
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.
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.
Cell Rep. 2015 Nov 10;13(6):1073-1080. doi: 10.1016/j.celrep.2015.09.065. Epub 2015 Oct 29.
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.
脑源性神经营养因子（BDNF）在能量平衡中起关键作用。在人群研究中，BDNF基因座的单核苷酸多态性（SNP）与肥胖有关，但这些变异导致体重增加的机制尚不清楚。在此，我们研究了人类下丘脑BDNF表达与44个BDNF SNP的相关性。我们观察到，rs12291063的次要C等位基因与人类腹内侧下丘脑BDNF表达降低相关（p < 0.001），并且在成人和儿童队列中均与更高的肥胖程度相关（p值 < 0.05）。我们进一步证明，rs12291063的主要T等位基因对转录调节因子异质性核糖核蛋白D0B具有结合能力，敲低该因子会破坏T等位基因的反式激活。用C替代T会破坏结合和反式激活功能。这些发现为在具有rs12291063 CC基因型的个体中增加BDNF作为肥胖的靶向治疗提供了理论依据。
