Xu Yuejie, Chen Ying, Bai Ningning, Su Yingying, Ye Yafen, Zhang Rong, Yang Ying, Liu Caizhi, Hu Cheng, Pan Jiemin
Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
Jinzhou Medical University Graduate Training Base (Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine), Jinzhou, 121001, China.
Mol Metab. 2025 Jun;96:102139. doi: 10.1016/j.molmet.2025.102139. Epub 2025 Apr 4.
The activation of brown adipose tissue (BAT) promotes energy expenditure is recognized as a promising therapeutic strategy for combating obesity. The deubiquitinating enzyme family members are widely involved in the process of energy metabolism. However, the specific deubiquitinating enzyme member that affects the BAT thermogenesis remains largely unexplored.
Adeno-associated virus, lentivirus and small molecule inhibitor were applied to generate USP2 gain- or loss-of-function both in vivo and in vitro. OxyMax comprehensive laboratory animal monitoring system, seahorse and transmission electron microscopy were used to determine the energy metabolism. Quantitative proteomics, immunofluorescence staining and co-immunoprecipitation were performed to reveal the potential substrates of USP2.
USP2 is upregulated upon thermogenic activation in adipose, and has a close correlation with UCP1 mRNA levels in human adipose tissue. BAT-specific Usp2 knockdown or systemic USP2 inhibition resulted in impaired thermogenic programs both in vivo and in vitro. Conversely, overexpression of Usp2 in BAT conferred protection against high-fat diet-induced obesity and associated metabolic disorders. Proteome-wide analysis identified EBF2 as the substrate of USP2 that mediates the thermogenic function of USP2 in BAT.
Our data demonstrated the vital role of USP2 in regulating BAT activation and systemic energy homeostasis. Activation of USP2-EBF2 interaction could be a potential therapeutic strategy against obesity.
棕色脂肪组织（BAT）的激活促进能量消耗，这被认为是对抗肥胖的一种有前景的治疗策略。去泛素化酶家族成员广泛参与能量代谢过程。然而，影响BAT产热的具体去泛素化酶成员在很大程度上仍未被探索。
应用腺相关病毒、慢病毒和小分子抑制剂在体内和体外产生USP2功能获得或功能缺失。使用OxyMax综合实验动物监测系统、海马体和透射电子显微镜来测定能量代谢。进行定量蛋白质组学、免疫荧光染色和免疫共沉淀以揭示USP2的潜在底物。
脂肪组织在产热激活时USP2上调，并且与人类脂肪组织中UCP1 mRNA水平密切相关。BAT特异性敲低Usp2或全身性抑制USP2在体内和体外均导致产热程序受损。相反，在BAT中过表达Usp2可预防高脂饮食诱导的肥胖及相关代谢紊乱。全蛋白质组分析确定EBF2是USP2的底物，其介导USP2在BAT中的产热功能。
我们的数据证明了USP2在调节BAT激活和全身能量稳态中的重要作用。激活USP2-EBF2相互作用可能是对抗肥胖的一种潜在治疗策略。
