Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Redox Biol. 2024 Feb;69:103013. doi: 10.1016/j.redox.2023.103013. Epub 2023 Dec 28.
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.
肥胖是一种复杂的代谢紊乱，表现为体脂肪的过度积累。Ten-Eleven Translocation-2（TET2）在肥胖领域引起了广泛关注，因为它在表观遗传调控和代谢平衡中起着关键作用。在这项研究中，我们旨在研究内皮细胞 TET2 对肥胖的影响，并探讨其潜在机制。我们生成了内皮细胞特异性 TET2 缺失小鼠，并通过转录组学和表观基因组学分析研究了内皮细胞 TET2。我们发现白色脂肪组织中内皮 TET2 的表达下调。此外，我们发现内皮 TET2 的缺失通过抑制血管生成从而抑制白色脂肪组织褐变，加重高脂肪饮食诱导的肥胖。机制上，内皮 TET2 通过参与内皮脂肪酸氧化和血管生成因子骨形态发生蛋白 4（BMP4）的分泌来调节肥胖，其中核因子-红细胞 2 相关因子 2（NRF2）作为关键介质。我们的研究揭示了内皮 TET2 通过与 NRF2 相互作用调节白色脂肪组织褐变，促进脂肪细胞的脂肪酸氧化和脂肪分解。
