# Immunological Memory of Obesity

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

## Abstract

Obese adipose tissue (AT) is insulin resistant and inflamed due to changes in the number and activation
state of innate and adaptive immune cells. Our single cell RNAseq studies of AT immune cells from lean and
obese mice confirm these immunophenotypes. A greater proportion of Veteran than Civilian populations are
obese, and while it is well-established that obesity increases risk of many diseases, recent evidence suggests
that the cycling of body weight further increases risk of cardiometabolic diseases. We developed a mouse model
of weight cycling (WC) and demonstrate that WC mice are more glucose intolerant than equally obese mice that
have not cycled. Furthermore, we show that WC amplifies the accumulation of many inflammatory immune
populations in AT beyond that of obese controls. Clues as to how WC increases AT inflammation can be gleaned
from animals that have lost weight. As expected, weight loss (WL) improves systemic insulin action; however,
the immune landscape of AT becomes even more inflammatory. We postulate that residual inflammatory cells
in AT after WL become hyperactivated upon subsequent weight regain, and lead to exaggerated inflammation
and metabolic dysfunction evident with WC. We and others have reported that the accumulation of AT T cells
(ATTs) in obesity is characterized by clonal expansion of CD8+ cells. Strikingly, our preliminary studies show that
WL and WC further amplify the number of clonally expanded CD8+ ATTs. Interestingly, the clonally expanded
cells have an exhausted phenotype, are not cytotoxic, and display high expression of granzyme K (Gzmk).
Although much less in known about Gzmk than other members of the granzyme family, our AT TGzmk cells are
remarkably similar to a subset of Gzmk-expressing CD8+ T cells that accumulate in multiple tissues in aged mice.
Additionally, a novel function of Gzmk – the ability to induce senescence in fibroblasts – suggests a potential
mechanistic link between Gzmk action and dysfunctional tissue aging. Cell senescence is often studied in aging
and cancer; however, emerging research suggests a role for adipocyte senescence in obesity and diabetes in
mice and humans. Our preliminary data confirm a senescent phenotype of adipocytes in obesity and WC, as
well as with Gzmk treatment. However, we do not know the importance of Gzmk or TGzmk cells in driving adipocyte
senescence or to the metabolic dysfunction of AT in obesity, WL, and WC. Taken together, these published and
preliminary studies lead us to hypothesize that TGzmk cells induce adipocyte senescence in obesity, which is
amplified upon weight loss and regain, promoting AT dysfunction and glucose intolerance with WC. Specific Aim
1. To determine the role of Gzmk in adipocyte senescence and AT dysfunction. Specific Aim 2. To determine
whether absence of Gzmk-expressing T cells reduces adipocyte senescence. Specific Aim 3. To determine
whether TGzmk cells are sufficient to induce adipocyte senescence and AT dysfunction. IMPAC...

## Key facts

- **NIH application ID:** 10695636
- **Project number:** 2I01BX002195-09A1
- **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:** 2
- **Project period:** 2014-07-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10695636

## Citation

> US National Institutes of Health, RePORTER application 10695636, Immunological Memory of Obesity (2I01BX002195-09A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10695636. Licensed CC0.

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