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

Cell Metab. 2016 Oct 11;24(4):542-554. doi: 10.1016/j.cmet.2016.08.010. Epub 2016 Sep 15.

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 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.

Keywords: DNA demethylation; Prkaa1; brown adipogenesis.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Adipogenesis / genetics*
  • Adipose Tissue, Brown / metabolism*
  • Adipose Tissue, Brown / ultrastructure
  • Animals
  • Cell Line
  • DNA Methylation / genetics*
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Gene Deletion
  • Ketoglutaric Acids / metabolism*
  • Mice, Knockout
  • Mice, Obese
  • Obesity / genetics
  • Promoter Regions, Genetic*
  • Stromal Cells / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Weaning

Substances

  • DNA-Binding Proteins
  • Ketoglutaric Acids
  • Prdm16 protein, mouse
  • Transcription Factors
  • AMP-Activated Protein Kinases