SDCCAG3 inhibits adipocyte hypertrophy and improves obesity-related metabolic disorders via SDCCAG3/SMURF1/PPARγ axis.

Obesity is a prevalent global disease associated with various metabolic disorders. The expansion of white adipose tissue plays a pivotal role in regulating obesity-related metabolic dysfunctions. This study identified serum-defined colon cancer antigen 3 (SDCCAG3) as a novel key modulator of adipocyte metabolism. In adipose-specific SDCCAG3 knockout mice fed a high-fat diet, pathological expansion of adipose tissue, impaired glucose tolerance, insulin resistance, increased inflammatory markers, and augmented hepatic lipid accumulation were observed. Conversely, obesity models by specific overexpression of SDCCAG3 in adipose tissue confirmed that SDCCAG3 alleviated pathological expansion of adipose tissue, improved obesity-related metabolic disorders, with no observed changes in adipose tissue development under normal dietary conditions. Mechanistically, SDCCAG3 enhanced the stability of peroxisome proliferator-activated receptor gamma (PPARγ) by preventing its degradation via the ubiquitin-proteasome system through the SMAD specific E3 ubiquitin protein ligase 1 (SMURF1). Additionally, SDCCAG3 was subjected to negative transcriptional regulation by PPARγ, forming a SDCCAG3-PPARγ-SDCCAG3 loop that enhanced adipocyte lipid metabolism. Collectively, these findings demonstrated that SDCCAG3 functioned as a beneficial positive regulator of adipose tissue expansion and metabolic homeostasis, indicating its potential as a therapeutic target for metabolic diseases associated with nutrient excess.