Thrap3 docks on phosphoserine 273 of PPARγ and controls diabetic gene programming

Area of Science:

• Molecular Endocrinology
• Metabolic Diseases

Background:

• Phosphorylation of peroxisome proliferator-activated receptor γ (PPARγ) at Ser273 by cyclin-dependent kinase 5 (CDK5) in adipose tissue is linked to insulin resistance.
• The precise molecular mechanisms underlying this process remain incompletely understood.

Purpose of the Study:

• To investigate the role of thyroid hormone receptor-associated protein 3 (Thrap3) in the context of PPARγ phosphorylation and insulin resistance.
• To elucidate the molecular interactions and gene regulatory networks involved.

Main Methods:

• Investigated the direct interaction between Thrap3 and phosphorylated PPARγ (pPPARγ) using cell-based assays.
• Utilized Thrap3 knockdown in cultured adipocytes to assess its impact on gene expression.
• Administered antisense oligonucleotides (ASOs) targeting Thrap3 in high-fat-fed mice to evaluate in vivo effects on metabolic parameters and gene expression.

Main Results:

• Thrap3 directly interacts with pPPARγ (at Ser273), mediating the effects of CDK5-induced PPARγ phosphorylation on gene expression.
• Thrap3 knockdown in adipocytes reversed most gene expression changes induced by CDK5-mediated PPARγ phosphorylation.
• In vivo reduction of Thrap3 expression in mice improved hyperglycemia and insulin resistance, affecting key adipokines like adiponectin and adipsin without altering body weight.

Conclusions:

• Thrap3 is a critical regulator of diabetic gene programming influenced by PPARγ phosphorylation.
• Targeting Thrap3 presents a potential therapeutic strategy for obesity and type 2 diabetes.