Obesity disrupts cholesterol metabolism in key immune cells, driving metabolic disease

New research reveals how obesity impairs the function of crucial regulatory T cells in fatty tissue by disrupting their cholesterol metabolism, potentially opening new therapeutic avenues for treating obesity-related metabolic disorders.

 

Molecular mechanism uncovered

Scientists have discovered that obesity interferes with cholesterol metabolism in a specific subset of regulatory T cells (Tregs) that reside in visceral fat tissue, leading to increased inflammation and insulin resistance. The groundbreaking study, published in Science Immunology on 10 January 2025, demonstrates how disrupting cholesterol homeostasis specifically affects ST2-expressing Tregs in visceral adipose tissue (VAT).

The research team, led by Dr Chaoran Li at Emory University School of Medicine, found that deleting the cholesterol regulator Srebf2 in VAT Tregs, or feeding mice a high-fat diet, impaired the accumulation of these crucial immune cells. Importantly, restoring normal cholesterol metabolism rescued the population of VAT Tregs in obese mice.

Critical role of cholesterol metabolism

“Our study establishes Srebf2-mediated cholesterol synthesis as a key metabolic pathway specifically important for the accumulation of VAT but not other tissue Tregs,” explain the authors in their paper. The research showed that Srebf2 controls both the composition and TCR repertoire of distinct Treg subsets in visceral fat.

The team demonstrated that cholesterol metabolism is particularly important for ST2-expressing Tregs, which play a vital role in maintaining metabolic health. When mice lacking Srebf2 in their Tregs were fed a high-fat diet, they developed more severe inflammation in their visceral fat tissue and showed greater insulin resistance compared to normal mice.

Therapeutic implications

“Our data indicate that HFD-induced disruption of cholesterol homeostasis promotes VAT Treg loss during obesity,” note the authors. They found that expression of crucial genes involved in cholesterol biosynthesis and uptake was reduced in VAT Tregs after 16 weeks of high-fat diet feeding.

Notably, the researchers discovered that restoring cholesterol homeostasis could rescue VAT Treg populations in obese mice, suggesting a potential therapeutic strategy. The study also revealed that human VAT Tregs showed similar disruptions in cholesterol metabolism that correlated with increasing body mass index.

This research provides new insights into how obesity affects immune function and metabolic health at the molecular level. The findings suggest that targeting cholesterol metabolism in VAT Tregs could potentially help treat obesity-related metabolic diseases.

“These results underscore the potential therapeutic promise of selectively modulating VAT Treg metabolism as a strategy for treating obesity-related ailments,” the authors note in their discussion.

Reference:

Elkins, C., Ye, C., Sivasami, P., Mulpur, R., et. al. (10 January 2025). Obesity reshapes regulatory T cells in the visceral adipose tissue by disrupting cellular cholesterol homeostasis. Science Immunology, 10(1), eadl4909. doi: https://doi.org/10.1126/sciimmunol.adl4909