Increasing the thermogenic capacity of adipose tissue to enhance organismal energy expenditure is considered a promising therapeutic strategy to combat obesity. Here, we report that ubiquitin-specific protease 2 (USP2), a member of the deubiquitinating enzyme family, plays regulatory roles in obesity progression. Expression of USP2 is down-regulated in the white adipose tissue of obese individuals and high-fat diet (HFD)-induced or genetically obese mice. When challenged with HFD, adipose-specific USP2 overexpression mice exhibited increased energy expenditure and thermogenic capacity, protecting mice against diet-induced obesity and the development of diabetes. In contrast, mice knocked down of USP2 expression or administered the USP2-specific inhibitor ML364 showed adverse trends regarding adipose accumulation and glucose metabolic disorders. Mechanistically, we demonstrate that, USP2 stimulate adipose thermogenesis by interacting with and deubiquitinating the transcription factor early B cell factor-2 (EBF2), which promotes thermogenic gene transcription through increasing the expression and activity of ERRα and PGC1α. Overall, our findings reveal for the first time an indispensable role of USP2 in thermogenesis and systemic homeostasis through EBF2 stabilization.
Y. Xu: None. J. Pan: None. C. Hu: None.
