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

Zongyang Mou,Gladys I Palaguachi,Eva Morgun,Thomas M Hyde,Jack W Tsao,Keri Martinowich,Alan B Zonderman,Peter Wei,Jack A Yanovski,Amanda J Krause,Stuart Maudsley,Andrew P Demidowich,Shelley A Cole,Joan C Han,Leslie J Marshall,Nancy F Butte,Karin Haack,Joel E Kleinman,Michele K Evans,Michael A Nalls,Bronwen Martin,Anthony G Comuzzie,Rujia Teng,Chen Lai,Barbara K Lipska,V Saroja Voruganti,Chiew Jen Ong ,Lindsay Hunter ,Tania Condarco ,Andrew Singleton

doi:10.1016/j.celrep.2015.09.065

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.

Highlights

Genetic factors play a role in the predisposition to obesity (Loos, 2012), and in the effectiveness of obesity treatments (Choquet and Meyre, 2011)
We examined the association of the brainderived neurotrophic factor (BDNF) locus SNPs with human ventromedial hypothalamus (VMH) BDNF expression and body composition in multiple pediatric and adult cohorts
We investigated the mechanistic role of intronic SNP rs12291063, which emerged as the strongest predictor of hypothalamic BDNF expression and body mass index (BMI)

Summary

Graphical Abstract

Han. 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 beneficial for treating obesity in individuals with the CC genotype.

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EXPERIMENTAL PROCEDURES