Wang Pengchao, Zhu Jingbo, Yang Liuye, Wang Yilong, Liang Minglu, Li Fengcen, Wang Ze, Liu Kaiyuan, Ai Mingfa, Li Dazhu, Huang Kai, Du Meng
Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Diabetes. 2025 Jul 1;74(7):1153-1167. doi: 10.2337/db24-1011.
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.
肥胖是日益严重的全球健康威胁，诱导白色脂肪组织（WAT）褐变以增加能量消耗已成为治疗肥胖及相关代谢并发症的一种有吸引力的策略。BRCA1相关蛋白1（BAP1）是一种在组织中广泛表达的含泛素C末端水解酶结构域的去泛素化酶，此前已证明其在肝脏碳水化合物和脂质代谢中起重要作用。然而，其在腹股沟WAT（iWAT）褐变中的作用尚未得到研究。我们的研究最初发现，在冷诱导的小鼠iWAT中BAP1表达下调，但在肥胖条件下上调。此外，腹股沟脂肪组织中BAP1的过表达抑制了iWAT褐变和产热。机制上，我们发现BAP1与KDM1B相互作用并通过去泛素化使其稳定。随后，KDM1B使产热相关基因附近的H3K4me1/2修饰去甲基化，从而抑制褐变所必需的基因表达。总之，我们的研究表明BAP1通过由KDM1B介导的机制负向调节iWAT褐变。
BRCA1相关蛋白1（BAP1）的表达在产热刺激下降低，而在肥胖情况下增加。小鼠腹股沟白色脂肪组织中BAP1的敲低导致肥胖及相关代谢紊乱的改善，这一效应归因于产热增强。BAP1通过去泛素化增加KDM1B的稳定性，使KDM1B通过消除组蛋白H3K4me1/2修饰来调节褐变相关基因的表达。ASXL2对于BAP1与KDM1B之间的相互作用以及KDM1B在组蛋白修饰中的功能至关重要。
