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Obesity disrupts cellular cholesterol homeostasis to inhibit the homeostatic clonal expansion of ST2hi VAT Treg cells

GSE243563 Mus musculus Expression profiling by high throughput sequencing; Other 4 samples Submitted 2025/01/10 Platform GPL24247
Summary
Regulatory T (Treg) cells are highly enriched in the visceral adipose tissue (VAT) to maintain metabolic homeostasis, but they are lost during obesity. Currently, how VAT Treg cells rewire cellular metabolism to support their homeostatic clonal expansion, and whether this process is disrupted in obesity, is unclear. Here, we found that cholesterol metabolism was uniquely upregulated in VAT-, but not other non-lymphoid-tissue Treg cells. Disrupting cholesterol homeostasis (CH) by Treg-specific deletion of Srebf2 led to a specific loss of VAT Treg cells and enhanced obesity-induced systemic metabolic dysfunction. Mechanistically, Srebf2-mediated CH potentiated strong TCR signaling, which specifically promoted the clonal expansion of ST2hi, but not other, VAT Treg subsets. However, long-term high-fat-diet feeding disrupted VAT Treg CH and impaired ST2hi VAT Treg clonal expansion. Restoring Treg CH rescued VAT Treg accumulation in obese mice, suggesting CH modulation could be a potential option for Treg-targeted therapies in obesity-associated metabolic diseases.
Published in
Obesity reshapes regulatory T cells in the visceral adipose tissue by disrupting cellular cholesterol homeostasis
Elkins C, Ye C, Sivasami P et al. · Science immunology 2025 · PMID 39792637 · doi:10.1126/sciimmunol.adl4909
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Also filed as BioProject PRJNA1018934 and SRA study SRP461884. Searching any of these in the dataset finder brings you back here.

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