Thyroid hormone receptor alpha sumoylation modulates white adipose tissue stores

Area of Science:

• Endocrinology
• Molecular Biology
• Cell Biology

Background:

• Thyroid hormone (TH) and its receptor (THR) are vital for stem cell regulation and tissue repair.
• Posttranslational modification, specifically SUMOylation, of THR influences its function.
• Understanding THR sumoylation's role in adipogenesis is critical for metabolic research.

Purpose of the Study:

• To investigate the in vivo and in vitro effects of thyroid hormone receptor alpha (THRA) sumoylation on adipocyte biology.
• To elucidate the molecular mechanisms by which THRA sumoylation impacts preadipocyte proliferation and cell cycle progression.
• To assess the role of THRA sumoylation in regulating white adipose tissue mass and adipocyte size.

Main Methods:

• Generation of a THRA sumoylation mutant mouse model (THRA K283Q/K288R-/-).
• In vitro studies using human primary preadipocytes and isolated preadipocytes from mutant mice.
• In vivo preadipocyte proliferation assessment using EdU labeling and chromatin immunoprecipitation (ChIP) assays.

Main Results:

• THRA mutant mice exhibited reduced white adipose stores and smaller adipocyte diameter on both chow and high-fat diets.
• Mutant mice showed impaired preadipocyte proliferation, with disruptions in G1/S cell cycle transition.
• Reduced CREB binding to CRE elements was observed in the THRA sumoylation mutant, affecting key cell cycle gene expression.

Conclusions:

• THRA sumoylation is essential for normal adipocyte proliferation and the maintenance of white adipose tissue.
• Disruption of THRA sumoylation leads to cell cycle dysregulation and reduced adipogenesis.
• The findings highlight a novel regulatory mechanism of THRA in metabolic homeostasis via CREB-mediated gene expression.