IMMUNOLOGY2024™ Conference Recordings-Obesity disrupts cholesterol homeostasis to specifically impair TCR-driven ST2hi VAT Treg accumulation and insulin sensitivity

Obesity disrupts cholesterol homeostasis to specifically impair TCR-driven ST2hi VAT Treg accumulation and insulin sensitivity

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Video Summary

The speaker studied how obesity affects regulatory T cells (Tregs) in visceral adipose tissue (VAT), especially the ST2-high subset that helps maintain anti-inflammatory, metabolically healthy fat. In obese mice, VAT Tregs lose cholesterol-homeostasis genes and have lower cellular cholesterol. VAT Tregs normally show high cholesterol uptake and biosynthesis, driven by SREBP2. Deleting SREBF2 specifically in Tregs reduced VAT Treg numbers, especially ST2-positive cells, but had little effect in the spleen. Under high-fat diet, these knockout mice showed more VAT inflammation, macrophage infiltration, cytokine production, and insulin resistance. Single-cell and TCR-sequencing analyses showed that ST2-high VAT Tregs are the most clonally expanded and are preferentially lost when cholesterol is disrupted. Reduced cholesterol also weakened TCR signaling. Stronger TCR stimulation favored ST2-high differentiation. Finally, blocking cholesterol export with ABCG1 knockout helped rescue VAT Treg accumulation in high-fat diet mice.

Keywords

obesity

regulatory T cells

visceral adipose tissue

cholesterol homeostasis

insulin resistance