ATF4 mediates cold-induced adipose tissue browning by regulating MTHFD2 expression

In mammals, adaptation to cold environments involves browning of inguinal white adipose tissue (iWAT) to enhance adaptive thermogenesis and maintain body temperature. Immune cells that reside in the adipose tissue are involved in iWAT browning. However, the mechanism by which thermogenesis regulates immune cell composition remains elusive. Here, we revealed that cold-induced activating transcription factor 4 (ATF4) is necessary for maintaining the immune cell composition and supporting iWAT browning. ATF4 and integrated stress response-related genes were highly expressed in iWAT following acute cold exposure. Mice lacking ATF4 exhibited less cold-induced iWAT browning and lower CL316,243-induced oxygen consumption. Mechanistically, the depletion of ATF4 leads to the accumulation of mitochondrial oxidative stress due to the reduction of MTHFD2, a mitochondrial one-carbon metabolism enzyme that contributes to the maintenance of the mitochondrial redox balance. This leads to higher levels of pro-inflammatory cytokines and shifts in adipose tissue macrophage polarization. Together, our findings highlight the critical role of ATF4 in maintaining oxidative stress and adipose tissue inflammatory signaling, thus supporting iWAT browning.