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

## TL;DR

The study explores how obesity affects protein regulation in fat tissue, revealing that STEAP4 is degraded through ubiquitination and linked to mitochondrial dysfunction in fat cells.

## Contribution

The first combined proteomic and ubiquitylomic analysis of murine visceral adipose tissue in obesity, identifying STEAP4 as a key target.

## Key findings

- STEAP4 protein levels are reduced with increased K48-linked ubiquitination in obese visceral adipose tissue.
- STEAP4 knockdown in adipocytes impairs mitochondrial function, suggesting a role in obesity-related dysfunction.

## Abstract

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.

•Combined proteome and ubiquitylome analysis of visceral adipose tissue during obesity.•STEAP4 is degraded via ubiquitin-proteasome in visceral adipose tissue during obesity.•STEAP4 knockdown impairs adipocyte mitochondrial function, indicating therapeutic value.

Combined proteome and ubiquitylome analysis of visceral adipose tissue during obesity.

STEAP4 is degraded via ubiquitin-proteasome in visceral adipose tissue during obesity.

STEAP4 knockdown impairs adipocyte mitochondrial function, indicating therapeutic value.

This study presents the combined proteomic and ubiquitylomic analysis of visceral adipose tissue in lean and obese mice, identifies ubiquitination-mediated STEAP4 downregulation in obesity, and links STEAP4 to adipocyte mitochondrial function, offering obesity therapeutic insights.