# Adipose-tissue Tregs: important players in immunological control of metabolism

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2021 · $423,750

## Abstract

Over the last three decades, there has been a striking rise in obesity, together with parallel increases in
insulin resistance, type-2 diabetes, cardiovascular disease and certain cancers. A critical link between obesity
and its downstream comorbidities is chronic low-grade inflammation promoted by secretion of pro-inflammatory
mediators by “angry” adipocytes and macrophages in visceral adipose tissue (VAT). Anti-inflammatory cells
and molecules capable of reining in these processes remain poorly understood. In 2009, we reported a
population of Foxp3+CD4+ regulatory T cells (Tregs) that is highly enriched in epididymal VAT (eVAT), but not
in lymphoid or other nonlymphoid organs, of lean mice as they age. These cells have a distinct gene-
expression profile, T cell receptor (TCR) repertoire and profile of mediator dependencies. eVAT Tregs are
strikingly and specifically reduced in several insulin-resistant mouse models of obesity, and loss- and gain-of-
function experiments have confirmed that they regulate local and systemic inflammation and metabolism. An
analogous Treg population is present in human omentum. eVAT Tregs serve as a paradigm for Treg
populations specifically adapted to survive and function within particular tissue environments.
 Over the last funding cycle, we made substantial strides in illuminating the biology of VAT Tregs: dissecting
transcriptome modulation with age and diet; discovering a two-step, two-site scenario of diversification from
lymphoid-organ Tregs; uncovering modes of molecular diversification, including the construction of a tissue-
Treg transcription-factor network; and demonstrating dependencies on TCR specificity, Foxp3 and IL-33.
 Building on these findings, the overall goal of this proposed project is to elucidate newly uncovered
cellular and molecular elements controlling the generation, homeostasis or function of eVAT Tregs. We
will undertake three Specific Aims, each designed to address a hypothesis that emerged from results obtained
during the last funding cycle.
1) To examine the precursor potential of the splenic PPARγlo Treg compartment.
2) To identify factors that elicit, promote or guide the splenic PPARγlo precursors of eVAT PPARγhi
Tregs.
3) To determine whether and how the homeostasis and function of eVAT Tregs are influenced by a
circadian clock.
 These studies should yield important new information on cellular and molecular pathways involved in
regulating the devastating downstream consequences of obesity. Identification of novel therapeutic targets
within these pathways is especially important given the disconcerting increases in these disorders and the
unacceptable side-effects of certain drug options.

## Key facts

- **NIH application ID:** 10149290
- **Project number:** 5R01DK092541-11
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** DIANE J MATHIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $423,750
- **Award type:** 5
- **Project period:** 2011-07-12 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10149290

## Citation

> US National Institutes of Health, RePORTER application 10149290, Adipose-tissue Tregs: important players in immunological control of metabolism (5R01DK092541-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10149290. Licensed CC0.

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