Brown adipose tissue (BAT) is critical for non-shivering thermogenesis making it a promising therapeutic strategy to combat obesity and metabolic disease. However, the regulatory mechanisms underlying brown fat formation remain incompletely understood. Here, we found SOX4 is required for BAT development and thermogenic program. Depletion of SOX4 in BAT progenitors (Sox4-MKO) or brown adipocytes (Sox4-BKO) resulted in whitened BAT and hypothermia upon acute cold exposure. The reduced thermogenic capacity of Sox4-MKO mice increases their susceptibility to diet-induced obesity. Conversely, overexpression of SOX4 in BAT enhances thermogenesis counteracting diet-induced obesity. Mechanistically, SOX4 activates the transcription of EBF2, which determines brown fat fate. Moreover, phosphorylation of SOX4 at S235 by PKA facilitates its nuclear translocation and EBF2 transcription. Further, SOX4 cooperates with EBF2 to activate transcriptional programs governing thermogenic gene expression. These results demonstrate that SOX4 serves as an upstream regulator of EBF2, providing valuable insights into BAT development and thermogenic function maintenance.

棕色脂肪组织 （BAT） 对于非颤抖产热至关重要，使其成为对抗肥胖和代谢疾病的一种有前途的治疗策略。然而，棕色脂肪形成的调节机制仍不完全清楚。在这里，我们发现 SOX4 是 BAT 开发和产热程序所必需的。BAT 祖细胞 （Sox4-MKO） 或棕色脂肪细胞 （Sox4-BKO） 中 SOX4 的耗竭导致急性寒冷暴露时 BAT 变白和体温过低。Sox4-MKO 小鼠的产热能力降低增加了它们对饮食诱导的肥胖的易感性。相反，在 BAT 中过表达 SOX4 会增强产热作用，抵消饮食诱导的肥胖。从机制上讲，SOX4 激活 EBF2 的转录，从而决定棕色脂肪的命运。此外，PKA 在 S235 位点对 SOX4 的磷酸化促进了其核转位和 EBF2 转录。此外，SOX4 与 EBF2 合作激活控制产热基因表达的转录程序。这些结果表明，SOX4 是 EBF2 的上游调节因子，为 BAT 发育和产热功能维持提供了有价值的见解。