# The importance of Treg-intrinsic cholesterol metabolism for visceral adipose tissue Treg homeostasis, phenotype, and function

> **NIH NIH F31** · EMORY UNIVERSITY · 2023 · $47,694

## Abstract

PROJECT SUMMARY
 Obesity has become major problem in western society, affecting ~40% of adults and 20% of children in
the US alone, according to the Center for Disease Control and Prevention (CDC). It is well known that obesity
can lead to insulin resistance, type II diabetes, and cardiovascular disease, termed “metabolic syndrome”, and
that obesity is a major risk factor for leading causes of preventable death such as heart attack and stroke. A key
factor driving metabolic disease in obesity is chronic low-grade inflammation in the visceral adipose tissue (VAT).
A population of regulatory T cells (Tregs), with a unique transcriptional signature and clonally expanded TCR
repertoire, is highly enriched in the VAT and plays an important role in controlling tissue inflammation. However,
this population is significantly reduced in obesity, which directly promotes VAT inflammation and symptoms of
metabolic disease. Multiple lines of evidence suggest that disruptions in cholesterol homeostasis (CH) is one
mechanism promoting a reduction in VAT Tregs during obesity. First, previously published data shows that
transcripts associated with CH are reduced in VAT Tregs following long-term high fat diet (HFD) feeding. Second,
preliminary data shows that Treg-specific loss of SREBP2 (Srebf2), the master regulator of CH, significantly
reduces Tregs in the VAT, but not in other tissues, at steady state and increases HFD-induced VAT inflammation
and insulin resistance. Finally, multiple subsets of VAT Tregs have been previously identified which differ in their
extent of T cell receptor (TCR) clonal expansion, and preliminary data also shows that Treg-specific loss of
SREBP2 alters the subset composition of the VAT Treg compartment, based on key surface markers, and
reduces antigen-induced expansion of VAT Tregs. Thus, this proposal hypothesizes that disrupting Treg-
intrinsic CH reduces VAT Treg proliferation by impairing TCR signaling and altering subset composition and
TCR clonal expansion. To test this, a unique TCR-transgenic mouse model containing a VAT-Treg derived TCR,
where Tregs preferentially accumulate in the VAT, will be utilized. Combining this model with ex vivo CRISPR-
Cas9 gene ablation and adoptive transfer, allows for the unique advantage of efficiently assessing the impact of
ablating genes of interest on VAT Treg accumulation. This model in conjunction with germline knockout models,
in vivo and in vitro assays, and single cell -omics approaches will allow for assessing the importance of cellular
CH in VAT Tregs. AIM 1 of this proposal will determine the mechanism by which disrupting Treg-intrinsic CH
impacts VAT Treg accumulation by assessing Srebf2-sufficient and -deficient VAT Treg proliferation, cell death,
and cell recruitment to the tissue, and by identifying the relative importance of cholesterol biosynthesis and
uptake for VAT Treg accumulation. AIM 2 will assess the impact of disrupting Treg-intrinsic CH on VAT Treg
TCR signaling and o...

## Key facts

- **NIH application ID:** 10752289
- **Project number:** 1F31DK137590-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** CODY ELKINS
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $47,694
- **Award type:** 1
- **Project period:** 2023-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10752289

## Citation

> US National Institutes of Health, RePORTER application 10752289, The importance of Treg-intrinsic cholesterol metabolism for visceral adipose tissue Treg homeostasis, phenotype, and function (1F31DK137590-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10752289. Licensed CC0.

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