Brown adipose tissue (BAT) is crucial for maintaining whole-body metabolic homeostasis and combating obesity and metabolic disorders. SOX4 collaborates with EBF2 to promote the expression of thermogenic genes in BAT, but it is unclear whether there are mechanisms independent of this regulation. However, it is found that SOX4 can directly interact with the promoter regions of thermogenic genes, thereby activating their expression. Simultaneously, early B cell factor 2 (EBF2) and peroxisome proliferator-activated receptor-γ (PPARγ) can independently interact with SOX4, forming two distinct complexes that promote the expression of thermogenic genes. Phenotypically, the deletion of SOX4 in BAT of mice ( Ucp1 Cre+ -Sox4 f/f ( Sox4-BKO )) leads to the downregulation of thermogenic and oxidative phosphorylation genes, as well as a reduction in mitochondrial numbers. Furthermore, Sox4-BKO mice are more susceptible to obesity, glucose intolerance, and insulin resistance when subjected to a high-fat diet (HFD). Consistently, the loss of SOX4 results in increased cellular triglyceride content and reduced expression levels of thermogenic genes in vitro. Together, a novel mechanism by which SOX4 regulates thermogenesis in BAT is elucidated, offering a promising strategy to address obesity and metabolic disorders.
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.
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