# Impact of the Adipose Tissue Microenvironment on Atherosclerosis

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2020 · $510,895

## Abstract

ABSTRACT
 Changes in the abundance and phenotypes of adipose tissue immune cells are a major determinant of
systemic inflammation and insulin resistance during excess weight gain. Adipocyte expression of the class II
major histocompatibility complex (MHCII) occurs early during high-fat diet (HFD) challenge and parallels pro-
inflammatory changes in MHCII-activated CD4+ adipose resident T cells (ARTs) implicating the adipocyte as
an instigator of obesity-induced inflammation. Adipocyte-specific MHCII null (aMHCII-/-) mice created to test
this hypothesis 1) developed substantially less visceral adipose tissue (VAT) inflammation than their wild-type
(WT) littermates when challenged with HFD, despite identical changes in body weight and %body fat, 2) had
markedly more VAT regulatory T cells (Tregs), but not in other peripheral sites; 3) were more insulin sensitive
with better glucose homeostasis and 4) when bred into an atherosclerosis prone LDLR-/- background,
attenuated accelerated atherosclerosis without affecting plasma cholesterol and triglyceride levels. Tregs are a
major component of the CD4+ ART population in lean mice, where they suppress inflammation to maintain
normal VAT metabolism, but dramatically decrease during HFD-challenge. However, VAT Tregs are preserved
in HFD-fed aMHCII-/- mice, which likely explains the improved metabolic and cardiovascular phenotype in these
mice. The aMHCII-/- mutation, thus, provides a unique opportunity to specifically alter adipose inflammation,
independent of obesity, dyslipidemia, and changes in peripheral T cells to investigate its impact on obesity-
induced complications, particularly atherosclerosis. We hypothesize that decreased adipose inflammation
attenuates atherosclerosis even in the presence of obesity. Specific Aims will address: 1) the effect of A)
aMHCII-deficiency and B) visceral adipose tissue (VAT)-specific Treg depletion (via cells with defective VAT
Treg homeostasis or an IL-33 receptor blocking antibody which inhibits IL-33-induced VAT Treg proliferation)
on diet-induced atherosclerosis; 2) whether A) constitutive, adipocyte-specific MHCII overexpression promotes
adipose inflammation to enhance atherosclerosis, and B) administration of IL-33 attenuates atherosclerosis
through a VAT Treg-dependent mechanism; and 3) changes in the immune cell composition and molecular
phenotypes in aortic lesions in mice with and without aMHCII mutations using T cell flow analyses of aorta,
laser capture microdissection of plaque macrophages, and investigation of macrophage trafficking from VAT to
aorta. The results of this investigation using adipocyte MHCII knock-in/knock-out models and several novel
approaches to specifically alter VAT, but not peripheral, Tregs will determine the contributions of adipose
tissue inflammation and VAT Tregs to the pathogenesis of obesity-associated atherosclerosis. This
mechanistic insight sets the stage for development of better immune-based therapeutic strategies to co...

## Key facts

- **NIH application ID:** 9838245
- **Project number:** 5R01HL135622-03
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Willa A Hsueh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $510,895
- **Award type:** 5
- **Project period:** 2017-12-15 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838245

## Citation

> US National Institutes of Health, RePORTER application 9838245, Impact of the Adipose Tissue Microenvironment on Atherosclerosis (5R01HL135622-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9838245. Licensed CC0.

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