Abstract
Obesity is a complex metabolic disorder, manifesting as excessive accumulation of body fat. Ten-Eleven Translocation-2 (TET2) has garnered significant attention in the context of obesity due to its crucial role in epigenetic regulation and metabolic homeostasis. In this study, we aimed to investigate the effect of endothelial TET2 on obesity and explore the potential mechanism. We generated endothelial cell-specific TET2 deficiency mice and investigated endothelial TET2 using transcriptomic and epigenomic analyses. We determined the downregulation of endothelial TET2 in white adipose tissues. Furthermore, we identified that endothelial TET2 loss aggravated high-fat diet-induced obesity by inhibiting vascularization and thus suppressing white adipose tissue browning. Mechanistically, endothelial TET2 modulates obesity by engaging in endothelial fatty acid oxidation and angiocrine-mediated secretion of bone morphogenetic protein 4 (BMP4), in which nuclear factor-erythroid 2-related factor 2 (NRF2) serves as a key mediator. Our study reveals that endothelial TET2 regulates white adipose tissue browning by interacting with NRF2 to facilitate fatty acid oxidation and lipolysis in adipocytes.