# Mechanisms of Adipose Tissue Immunoregulatory T cell (Treg) Exhaustion in Obesity

> **NIH NIH R56** · OHIO STATE UNIVERSITY · 2021 · $438,295

## Abstract

Project Abstract. Adipose tissue (AT) regulatory T cells (Tregs) are major determinants of systemic metabolism,
and in lean mice, protect against obesity-associated inflammation and complications. Tregs are key in
homeostatic maintenance in lean AT, but abundance profoundly decreases in obese AT leading to inflammation,
insulin resistance, and other inflammatory-driven complications. Our preliminary data suggests exhaustion
contributes to the loss of AT Tregs in obesity. AT vs. blood Tregs from obese humans reveal increased
expression of programmed cell death protein 1 (PD-1) and other inhibitory co-receptors (OX40, CTLA4); impaired
suppressive function, which is reversible; decreased liver kinase B1 (LKB1), which protects Tregs from
exhaustion; and increased methylation of the CNS2 in the FOXP3 locus suggesting instability. These
characteristics form our working definition of exhaustion. Moreover, RNAseq analyses of human AT PD-1 high
vs. negative cells revealed downregulation of 75% of significantly changed genes, including genes involved in
suppressor function, while upregulated genes included apoptosis and cell death genes. Furthermore, in cultured
human Tregs, interferon gamma (IFNG) stimulated expression of inhibitory co-receptors and apoptosis markers
and decreased LKB1 expression, suggesting it may mediate AT Treg exhaustion. These findings underscore the
need to investigate mechanisms regulating AT Treg abundance/function. Our Specific Aims include:
Aim 1. Hypothesis: Human obese AT Tregs are phenotypically exhausted, which contributes to the
decline in human AT Tregs during high fat diet (HFD) ingestion. We will: A) Determine whether there are
more exhausted Tregs in obese vs. lean AT; B) Utilize single cell (sc)RNAseq and Global DNA methylation to
define subpopulations of human lean and obese AT Tregs that may be exhausted; and C) Determine whether
pioglitazone will attenuate the HFD-induced AT Treg decline in lean humans by preventing exhaustion and
impacting AT Treg transcriptional changes.
Aim 2. Hypothesis: Interferon-gamma (IFNG), toxic lipids, and/or decreased Treg PPARγ activity are
mediators that contribute to exhaustion and declining Tregs in obesity. To determine whether
attenuation/knockout of specific pathways in Tregs (supported by evidence of in vivo metabolic changes) leads
to changes in AT Treg exhaustion, AT Treg abundance, and HFD-induced systemic insulin resistance, we will
use several mouse models predicted to promote Treg exhaustion: A) Treg-specific knockout of the IFNG receptor
(IFNGR1); B) Treg-specific loss of serine palmitoyl transferase 2 (encoded by Sptlc2), a rate limiting enzyme
required for ceramide biosynthesis; and C) Treg specific ablation of a key supportive factor for AT Tregs, PPARγ.
Taken together, these investigations will shed light on a new, potentially important mechanism explaining the
striking loss of AT Tregs that occurs with HFD and obesity.

## Key facts

- **NIH application ID:** 10454627
- **Project number:** 1R56AI157202-01A1
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** David Paul Bradley
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $438,295
- **Award type:** 1
- **Project period:** 2021-08-19 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10454627

## Citation

> US National Institutes of Health, RePORTER application 10454627, Mechanisms of Adipose Tissue Immunoregulatory T cell (Treg) Exhaustion in Obesity (1R56AI157202-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10454627. Licensed CC0.

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