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

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

来源：Cell Metabolism, 2016, 24(4): 542-554.

DOI：10.1016/j.cmet.2016.08.010

• EMBRYONIC STEM-CELLS
• ADIPOSE-TISSUE THERMOGENESIS
• INFANT-DEATH-SYNDROME
• IDH MUTATIONS
• METHYLATION
• CANCER
• FAT
• 5-HYDROXYMETHYLCYTOSINE
• EXPRESSION
• MITOCHONDRIA

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.

• 出版日期2016-10-11
• 单位中国农业科学院; 中国农业大学