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

Publication date: Available online 15 September 2016
Source:Cell Metabolism
Author(s): Qiyuan Yang, Xingwei Liang, Xiaofei Sun, Lupei Zhang, Xing Fu, Carl J. Rogers, Anna Berim, Shuming Zhang, Songbo Wang, Bo Wang, Marc Foretz, Benoit Viollet, David R. Gang, Buel D. Rodgers, Mei-Jun Zhu, Min Du
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 AMPKα1 (PRKAA1) ablation reduced Prdm16 expression and impaired BAT development. During early brown adipogenesis, the cellular levels of α-ketoglutarate (αKG), a key metabolite required for TET-mediated DNA demethylation, were profoundly increased and required for active DNA demethylation of the Prdm16 promoter. AMPKα1 ablation reduced isocitrate dehydrogenase 2 activity and cellular αKG 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 αKG, thus linking a metabolite to progenitor cell differentiation and thermogenesis.

Graphical abstract

Teaser

Yang et al. show that AMPK is essential for brown adipose tissue development through the elevation of α-ketoglutarate, which facilitates TET-mediated DNA demethylation of the Prdm16 promoter, committing progenitor cells to brown adipogenic differentiation. Postnatal AMPK activation by metformin rescues the obesity-induced attenuation of brown adipogenesis.


http://ift.tt/2cDBUG9