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

Area of Science:

• Metabolic disease research
• Adipocyte biology
• Molecular endocrinology

Background:

• Obesity is a global health issue linked to metabolic disorders.
• White adipose tissue expansion is central to obesity-related metabolic dysfunction.
• Identifying key regulators of adipocyte metabolism is crucial for therapeutic development.

Purpose of the Study:

• To identify novel modulators of adipocyte metabolism.
• To investigate the role of serum-defined colon cancer antigen 3 (SDCCAG3) in obesity and metabolic homeostasis.
• To elucidate the molecular mechanisms underlying SDCCAG3's function in adipose tissue.

Main Methods:

• Generation and analysis of adipose-specific SDCCAG3 knockout mice.
• Overexpression studies of SDCCAG3 in adipose tissue of obesity models.
• Investigation of SDCCAG3's interaction with peroxisome proliferator-activated receptor gamma (PPARγ) and the ubiquitin-proteasome system.
• Assessment of metabolic parameters including glucose tolerance, insulin resistance, and hepatic lipid accumulation.

Main Results:

• Adipose-specific SDCCAG3 knockout mice exhibited pathological adipose tissue expansion, impaired glucose tolerance, insulin resistance, increased inflammation, and hepatic lipid accumulation.
• Overexpression of SDCCAG3 in adipose tissue ameliorated obesity-related metabolic disorders and pathological adipose tissue expansion.
• SDCCAG3 stabilizes PPARγ by inhibiting its ubiquitination and proteasomal degradation via SMURF1.
• A feedback loop between SDCCAG3 and PPARγ was identified, enhancing adipocyte lipid metabolism.

Conclusions:

• SDCCAG3 is a novel positive regulator of adipose tissue expansion and metabolic homeostasis.
• SDCCAG3 plays a beneficial role in mitigating obesity-related metabolic dysfunctions.
• SDCCAG3 represents a potential therapeutic target for metabolic diseases driven by nutrient excess.