BAP1 Suppresses White Adipose Tissue Browning and Thermogenesis Through Deubiquitinating KDM1B

Obesity is a growing global health threat, and inducing browning of white adipose tissue (WAT) to increase energy expenditure has become an attractive strategy for treating obesity and related metabolic complications. BRCA1-associated protein 1 (BAP1), a ubiquitin C-terminal hydrolase domain-containing deubiquitinase expressed broadly across tissues, has previously been shown to play an important role in liver carbohydrate and lipid metabolism. However, its role in the browning of inguinal WAT (iWAT) has not been studied. Our study initially found that BAP1 expression was downregulated in cold-induced mouse iWAT but upregulated in obese conditions. Furthermore, overexpression of BAP1 in the inguinal fat tissue suppressed iWAT browning and thermogenesis. Mechanistically, we found that BAP1 interacts with KDM1B and stabilizes it through deubiquitination. Subsequently, KDM1B demethylates H3K4me1/2 modifications in proximity to thermogenesis-related genes, thereby inhibiting the expression of genes essential for browning. In summary, our study shows that BAP1 negatively regulates iWAT browning via a mechanism mediated by KDM1B.

The expression of BRCA1-associated protein 1 (BAP1) is decreased in response to thermogenic stimuli, while it is increased in the context of obesity. The knockdown of BAP1 in the inguinal white adipose tissue in mice leads to an amelioration of obesity and associated metabolic disorders, an effect attributed to enhanced thermogenesis. BAP1 increases the stability of KDM1B by deubiquitination, allowing KDM1B to regulate the expression of browning-related genes by erasing histone H3K4me1/2 modifications. ASXL2 is essential for the interaction between BAP1 and KDM1B, as well as for the function of KDM1B in histone modification.