# Cytokine and Metabolic Regulation of Adipose-tissue Tregs

> **NIH NIH R01** · EMORY UNIVERSITY · 2024 · $436,762

## Abstract

PROJECT SUMMARY
Over the last few decades, obesity-associated metabolic disorders, including insulin resistance, type-2
diabetes, and cardiovascular diseases, have become a major health burden, affecting up to a quarter of U.S.
adults. Chronic, low-grade inflammation of the visceral adipose tissue (VAT), which eventually leads to
systemic inflammation, is a major driver of obesity-induced metabolic abnormalities. However, the mechanisms
of the initiation and progression of obesity-induced inflammation are still poorly understood. A unique
population of Foxp3+ regulatory T cells (Tregs) with a distinct antigen receptor repertoire and transcriptional
profile accumulates in VAT of lean male mice and estrogen-deficient female mice, keeps the inflammation in
check, and promotes metabolic health. Obesity, however, leads to significant reduction of VAT Tregs and loss
of their distinct features, resulting in elevated inflammation and worsened metabolic outcomes. This obesity-
induced toxicity severely hinders the development of VAT-Treg-targeted strategies against metabolic
disorders. The overall goal of this proposed project is to use novel genetic and biochemical tools to uncover
the unique cytokine, metabolic, and sex-hormone-mediated mechanisms that control the homeostasis of VAT
Tregs at steady state, and to investigate how disruption of these pathways could contribute to obesity-induced
toxicity of VAT Tregs in both males and estrogen-deficient females. By tracing the dynamics and transcriptomic
changes of Tregs residing in the epidydimal VAT (eVAT) in a diet-induced obesity model, we identified that the
reduction of eVAT Tregs during long-term high-fat-diet (HFD) feeding is associated with induction of a type I
IFN signature and a concurrent loss of transcripts involved in the synthesis and uptake of cholesterol. Further
experiments showed that eVAT Tregs preferentially depend on cholesterol homeostasis, which is inhibited by
obesity-induced type I IFNs. In addition, we identified that VAT Tregs from female mice respond to obesity
differently from males in an estrogen-dependent manner. Building on these observations, we will elucidate the
mechanisms that control VAT Treg homeostasis and their response to obesity through three specific aims:
In Aim 1, we will elucidate the mechanisms by which elevated type I IFNs drive the decline of eVAT Tregs and
promote metabolic abnormalities during obesity.
In Aim 2, we will determine the specific role of cholesterol homeostasis in eVAT Tregs and how its perturbation
contributes to the dysregulation of eVAT Tregs during obesity.
In Aim 3, we will elucidate how VAT Tregs respond to obesity in females with disrupted estrogen signaling.
These efforts will support our long-term goal to better understand the mechanisms that drive immune
dysregulation in obesity-associated chronic diseases.

## Key facts

- **NIH application ID:** 10895290
- **Project number:** 5R01DK128061-04
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Chaoran Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $436,762
- **Award type:** 5
- **Project period:** 2021-09-17 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10895290

## Citation

> US National Institutes of Health, RePORTER application 10895290, Cytokine and Metabolic Regulation of Adipose-tissue Tregs (5R01DK128061-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10895290. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*