摘要：SummaryHealthy adipose tissue is crucial to maintain normal energy homeostasis. Little is known about the role of murine double minute 2 (MDM2), an E3 ubiquitin ligase and has been highlighted in oncopathology, in adipose tissue. Our results indicated that MDM2 expression was associated with nutritional status.Mdm2adipocyte-specific knock-in (Mdm2-AKI) mice exhibited exacerbated weight gain, insulin resistance, and decreased energy expenditure. Meanwhile, chronic high-fat diet (HFD) exposure caused obvious epididymal white adipose tissue (eWAT) dysfunction, such as senescence, apoptosis, and chronic inflammation, thereby leading to hepatic steatosis inMdm2-AKI mice. Mechanically, MDM2 could interact with six-transmembrane epithelial antigen of prostate 4 (STEAP4) and inhibit STEAP4 expression through ubiquitin-mediated STEAP4 degradation. Thereinto, the K18 and K161 sites of STEAP4 were ubiquitin-modificated by MDM2. Finally, STEAP4 restoration in eWAT ofMdm2-AKI mice on a HFD rescued MDM2-induced adipose dysfunction, insulin resistance, and hepatic steatosis. Summary, the MDM2-STEAP4 axis in eWAT plays an important role in maintaining healthy adipose tissue function and improving hepatic steatosis.Graphical abstractDisplay OmittedHighlights•Murine double minute 2 (MDM2) overexpression intensifies high-fat diet-induced adipose tissue dysfunction•Adipocyte MDM2 overexpression aggravates insulin resistance and hepatosteatosis•MDM2 decreases six-transmembrane epithelial antigen of prostate 4 (STEAP4) expression by ubiquitin-dependent STEAP4 degradation•STEAP4 overexpression in eWAT alleviates MDM2-induced metabolic disorderBiological sciences; Molecular biology; Immunology; Proteomics
