IDH2 links mitochondrial α-ketoglutarate to epigenetic thermogenic activation in brown adipose tissue

Abstract Brown adipose tissue (BAT) regulates energy expenditure, influencing metabolic health. This study aimed to highlight the role of isocitrate dehydrogenase 2 (IDH2), a mitochondrial enzyme essential for alpha-ketoglutarate (α-KG) production, in BAT differentiation and function. In global and BAT-specific IDH2 knockout (KO) mice, cold exposure reduced thermogenesis, induced BAT whitening, and abolished the cold-dependent induction of thermogenesis by reducing the expressions of key thermogenic genes. Lower α-KG levels in IDH2 KO BAT, a key cofactor for TET2-mediated conversion of 5-methylcytosine to 5-hydroxymethylcytosine in genomic DNA, decreased the nuclear factor erythroid-2-related factor 2 (NRF2)-dependent induction of BAT-enriched lncRNA 10 (lncBATE10). Reduced induction of thermogenesis in IDH2-deficient BAT impaired energy balance. α-KG supplementation partially restored TET2 function and thermogenic gene expression in IDH2 KO mice, indicating that IDH2-dependent α-KG production is an important contributor to the thermogenic response during cold exposure. Our study uncovers a previously unrecognized novel mechanism involving the IDH2–TET2–Nrf2–lncBATE10 regulatory axis, linking mitochondrial function to epigenetic BAT regulation.