AMPK/alpha-Ketoglutarate Axis Dynamically Mediates DNA Demethylation in the Prdm16 Promoter and Brown Adipogenesis

文献类型： 外文期刊

第一作者： Yang, Qiyuan

作者： Yang, Qiyuan;Liang, Xingwei;Zhang, Lupei;Fu, Xing;Rogers, Carl J.;Wang, Songbo;Wang, Bo;Rodgers, Buel D.;Du, Min;Yang, Qiyuan;Liang, Xingwei;Zhang, Lupei;Fu, Xing;Rogers, Carl J.;Wang, Songbo;Wang, Bo;Rodgers, Buel D.;Du, Min;Sun, Xiaofei;Zhang, Shuming;Zhu, Mei-Jun;Berim, Anna;Gang, David R.;Du, Min;Zhang, Lupei;Foretz, Marc;Viollet, Benoit;Foretz, Marc;Viollet, Benoit;Foretz, Marc;Viollet, Benoit

作者机构：

期刊名称：CELL METABOLISM （ 影响因子：27.287； 五年影响因子：30.767 ）

ISSN： 1550-4131

年卷期： 2016 年 24 卷 4 期

页码：

收录情况： SCI

摘要： Promoting brown adipose tissue (BAT) development is an attractive strategy for the treatment of obesity, as activated BAT dissipates energy through thermogenesis; however, the mechanisms controlling BAT formation are not fully understood. We hypothesized that as a master regulator of energy metabolism, AMP-activated protein kinase (AMPK) may play a direct role in the process and found that AMPK alpha 1 (PRKAA1) ablation reduced Prdm16 expression and impaired BAT development. During early brown adipogenesis, the cellular levels of a-ketoglutarate (alpha KG), a key metabolite required for TET-mediated DNA demethylation, were profoundly increased and required for active DNA demethylation of the Prdm16 promoter. AMPKa1 ablation reduced isocitrate dehydrogenase 2 activity and cellular alpha KG levels. Remarkably, postnatal AMPK activation with AICAR or metformin rescued obesity-induced suppression of brown adipogenesis and thermogenesis. In summary, AMPK is essential for the epigenetic control of BAT development through alpha KG, thus linking a metabolite to progenitor cell differentiation and thermogenesis.

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