Murine double minute 2 aggravates adipose tissue dysfunction through ubiquitin-mediated six-transmembrane epithelial...

Area of Science:

• Metabolic disease research
• Obesity and adipose tissue biology
• Molecular mechanisms of metabolic dysfunction

Background:

• Adipose tissue is vital for energy balance.
• The role of murine double minute 2 (MDM2), an E3 ubiquitin ligase, in adipose tissue is largely unknown.
• MDM2 is implicated in oncopathology.

Purpose of the Study:

• To investigate the role of MDM2 in adipose tissue.
• To elucidate the molecular mechanisms linking MDM2 to metabolic dysfunction.
• To explore therapeutic potential of targeting the MDM2-STEAP4 axis.

Main Methods:

• Generation and analysis of adipocyte-specific MDM2 knock-in (Mdm2-AKI) mice.
• High-fat diet (HFD) induction to model metabolic syndrome.
• Assessment of adipose tissue function, insulin resistance, energy expenditure, and hepatic steatosis.
• Investigation of MDM2-STEAP4 interaction and ubiquitination via molecular assays.
• STEAP4 restoration experiments in vivo.

Main Results:

• MDM2 expression correlates with nutritional status.
• Mdm2-AKI mice show increased weight gain, insulin resistance, and reduced energy expenditure.
• HFD exacerbates adipose tissue dysfunction (senescence, apoptosis, inflammation) and hepatic steatosis in Mdm2-AKI mice.
• MDM2 interacts with STEAP4, promoting its ubiquitination and degradation, thus inhibiting STEAP4 expression.
• STEAP4 restoration ameliorates MDM2-induced metabolic abnormalities.

Conclusions:

• The MDM2-STEAP4 signaling axis in epididymal white adipose tissue (eWAT) is critical for maintaining adipose tissue function.
• Dysregulation of this axis contributes to obesity, insulin resistance, and hepatic steatosis.
• Targeting the MDM2-STEAP4 interaction may offer a therapeutic strategy for metabolic disorders.