# Immunological Memory of Obesity

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2024 · —

## Abstract

Project Summary
Obesity now affects over 40% of the US population and is considered the most common chronic inflammatory
condition. This increase in prevalence can be attributed to more sedentary lifestyles in combination with easy
access to highly palatable, calorically dense foods. Health care providers often prescribe lifestyle modifications
to combat obesity and the negative metabolic and cardiovascular outcomes associated with this disease;
however, keeping adiposity at bay is often the greatest challenge faced by individuals. Many individuals find
themselves weight cycling — periods of repeated weight loss and weight regain for a significant portion of their
life, which leads to worsened glucose tolerance and cardiometabolic outcomes. The increase in adiposity that
accompanies obesity is characterized by recruitment of proinflammatory immune cells into the adipose tissue
that is not resolved with weight loss, suggesting that immune memory in adipose tissue contributes to diseases
associated with obesity. We have developed and characterized a robust model of weight cycling in mice and
observed that animals that weight cycle have worsened glucose tolerance compared to their non-weight cycled,
obese, weight-matched counterparts. In obesity, the adipose tissue is characterized by an increase in CD8+
effector memory T-cells that show signs of both exhaustion and memory. In Dr. Hasty’s parent funded Merit
award, the contribution of granzyme K expressing T cells to adipocyte senescence will be studied. In other work,
we have shown that this memory T cell population is clonally expanded suggesting that adipose tissue
“remembers” previous cycles of obesity, which may contribute to the worsened glucose tolerance seen in our
weight cycled animals. To test the hypothesis that T cell memory plays a role in the metabolic outcomes we
observe in weight cycling mice, Dr. Garcia has focused on the surface protein CD70, a ligand specific to antigen
presenting cells that binds to the CD27 receptor on T cells promoting T cell memory formation. Her preliminary
findings indicate that CD70-/- weight-cycled animals are protected from worsened glucose tolerance seen in the
wild-type littermates. Therefore, this application aims to identify whether inhibiting T cell memory formation during
the weight loss phase functions to prevent clonal expansion within the adipose tissue environment leading to
overall reduced inflammatory potential and prevention of the impaired metabolic phenotypes seen in wild-type
weight cycled mice. To determine the critical timing for memory formation, we will use a CD70 depletion antibody
during the weight gain or weight loss phases and observe whether mice treated with this antibody are protected
from worsened glucose tolerance. We will also use single cell RNA sequencing via the 10X Genomics Platform
on adipose tissue from CD70-/- and wild-type mice to determine how loss of CD70 impacts the immune cell milieu.
Ultimately, this work serves ...

## Key facts

- **NIH application ID:** 10879373
- **Project number:** 3I01BX002195-09A1S1
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Alyssa H Hasty
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 3
- **Project period:** 2014-07-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10879373

## Citation

> US National Institutes of Health, RePORTER application 10879373, Immunological Memory of Obesity (3I01BX002195-09A1S1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10879373. Licensed CC0.

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