Enhanced STEAP4 Ubiquitination in Obesity: Insights From Combined Proteome and Ubiquitylome Analysis of Visceral Adipose Tissue

Obesity remains a worldwide health issue, with visceral adipose tissue as a leading driver of this pathology. As the executors of biological functions in living cells, proteins have their activity regulated by diverse post-translational modifications, including ubiquitination. However, obesity-related changes in ubiquitination of visceral adipose tissue (VAT) proteins are still poorly understood. Here, we obtained the global proteomic and ubiquitylomic data of epididymal VAT from lean and obese male mice by mass spectrometry. Our proteomic analyses revealed significant changes of metabolic pathways involved in fatty acid, acyl-CoA and branched chain amino acids metabolism in obese VAT. Intriguingly, a comparative analysis of proteomic and ubiquitylomic data highlighted discordance in the quantity changes of certain proteins and their ubiquitination levels. Notably, STEAP4 exhibited a markedly reduced protein level coupled with an enhanced K48-linked ubiquitination, suggesting a potential role for ubiquitination-mediated proteasome degradation in VAT dysfunction. Further in vitro experiments revealed that knockdown of STEAP4 in adipocytes impaired mitochondrial function of 3T3-L1 adipocytes. Collectively, this study introduces the first combined proteomic and ubiquitylomic examination of murine VAT, offering novel insights and potential therapeutic targets for obesity.