USP25 deficiency suppresses diet-induced obesity via ubiquitination and degradation of PARP1 and Elovl3 downregulation

Ubiquitin-specific protease 25 (USP25) is a key regulator of lipid metabolism and insulin-stimulated glucose transport. Nonetheless, its involvement in adipocyte maturation remains uncertain. In this study, we aimed to explore how the expression of USP25 contributes to obesity induced by a high-fat diet (HFD). Usp25-knock-out (KO) and wild-type (WT) mice, maintained on either a normal diet (ND) or an HFD, were evaluated for weight gain, insulin resistance status, adipose tissue development, energy metabolism, and systemic inflammation status. In vitro, 3T3-L1 cells were induced to mature adipocytes in a specific culture medium. We found that USP25 expression decreased in obese mice subjected to long-term HFD feeding and in mature adipocytes. Usp25-KO mice showed restrained adipose tissue development and improved insulin resistance, whereas USP25-deficient preadipocytes failed to differentiate. RNA sequencing analysis showed the downregulation of lipid synthesis-related pathways in Usp25-KO mice. Mechanistically, USP25 binds to and stabilizes Poly (ADP-ribose) polymerase 1 (PARP1) through deubiquitination, while PARP1 facilitates pre-adipocyte differentiation and maturation by regulating the elongation of very long-chain fatty acids protein 3 (ELOVL3). These findings show the essential role of USP25 in adipocyte differentiation and lipid metabolism, suggesting that targeting USP25 ablation in adipocytes could be a promising therapeutic strategy for obesity treatment.