# The role of T cells in adipose tissue inflammation and insulin resistance during weight cycling

> **NIH NIH F31** · VANDERBILT UNIVERSITY · 2021 · $30,747

## Abstract

Project Summary
On average, people who successfully lose weight will regain 80% of the lost weight within 5 years.
Bouts of weight loss (WL) and weight regain, referred to as “weight cycling” (WC), are associated with
increased risk of cardiovascular disease and of development of type 2 diabetes mellitus in humans. To
identify causes and correlation of the progressive metabolic dysregulation observed in humans who
WC, we have developed a mouse model of WC in which alternating 60% high and 10% low-fat diets
robustly induce cycles of weight gain and WL. Glucose tolerance in WC animals is impaired compared
to age, weight, and adiposity-matched high-fat fed control animals. Alterations in systemic glucose
regulation is partially dependent on adaptive immune cells that infiltrate metabolic tissues, including
adipose tissue (AT), during progression of obesity. However, the phenotype of these important cells
during WL and WC has not been characterized. Premised on novel preliminary findings that CD8+ T
cells display markers of immunotolerance during WL and aggressive inflammatory potential during WC,
I hypothesize that AT CD8+ T cells transiently become tolerant during WL, but are potently
reactivated after WC and are necessary for impaired insulin sensitivity observed during WC. We
have observed a loss of T cell receptor diversity in visceral AT during obesity, indicating that T cells
clonally expand in response to a nutritionally-triggered antigen. To further elucidate the role that clonal
T cell expansion may play in systemic glucose handling in WL and WC mice, I will characterize T cells
with single-cell resolution using sequencing and flow cytometry-based approaches. Additionally, we will
use depletion and genetic models to block long-lived CD8+ T cells from contributing to glucose
intolerance observed during WC. Obesity-experienced CD8+ T cells will be depleted using monoclonal
antibodies prior to WL. After recovery, animals will again be challenged with diet-induced obesity to
identify if inexperienced CD8+ T cells are unable to promote insulin resistance characteristic of AT after
WC. Concomitantly, CD70-/- mice, which fail to maintain survival of activated T cells long-term, will be
WC and metabolically phenotyped to determine whether it is long-lived AT-resident CD8+ T cells that
are necessary for driving systemic glucose dysregulation. Both of these models will be phenotyped with
gold-standard hyperinsulinemic euglycemic clamps to expose differences in insulin sensitivity from
control mice. Ultimately, this proposal seeks to fill an unmet need in the metabolism and inflammation
fields regarding T cell phenotype and function during AT remodeling. As a result, the outcomes of this
project will influence subsequent work by providing clear insight into mechanisms of T-cell driven
inflammation and therapeutic targets for weight maintenance.

## Key facts

- **NIH application ID:** 10105191
- **Project number:** 5F31DK123881-02
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Matthew Alexander Cottam
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $30,747
- **Award type:** 5
- **Project period:** 2020-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10105191

## Citation

> US National Institutes of Health, RePORTER application 10105191, The role of T cells in adipose tissue inflammation and insulin resistance during weight cycling (5F31DK123881-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10105191. Licensed CC0.

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