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

ABSTRACT: 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?1 (PRKAA1) ablation reduced Prdm16 expression and impaired BAT development. During early brown adipogenesis, the cellular levels of ?-ketoglutarate (?KG), a key metabolite required for TET-mediated DNA demethylation, were profoundly increased and required for active DNA demethylation of the Prdm16 promoter. AMPK?1 ablation reduced isocitrate dehydrogenase 2 activity and cellular ?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 ?KG, thus linking a metabolite to progenitor cell differentiation and thermogenesis.

SUBMITTER: Yang Q 

PROVIDER: S-EPMC5061633 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature