SOX4 Regulates Thermogenesis in Brown Adipose Tissue via Independent Complexes with EBF2 and PPARγ

Abstract 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.