# Impact of Obesity on Lung Macrophage Metabolism and Inflammation

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2024 · $581,456

## Abstract

PROJECT SUMMARY/ABSTRACT
Obesity increases the risk of developing asthma in children and adults, and obesity-associated asthma (OAA) is
often more severe and more difficult to treat than atopic asthma. These poor clinical outcomes may stem from
OAA’s distinct immunopathology that includes differences in how lung immune cells respond to inflammatory
stimuli and a heterogeneous but neutrophil-predominant lung inflammation. Our limited understanding of how
obesity alters lung innate immune cell responses to inflammatory stimuli hinders the development of novel
preventative and therapeutic approaches for OAA. Obesity causes lipid deposition in the lung and lipid
accumulation in lung tissue resident macrophages (TRMs). These processes may contribute to OAA
immunopathology as TRMs are both intimately involved in asthma pathogenesis and sensitive to
immunometabolic reprogramming during obesity. Despite this, we do not know if lung TRMs adopt distinct
immunometabolic and functional programs as a result of obesity, or if obesity-associated lung TRMs contribute
to OAA. To begin to address this knowledge gap, we have performed preliminary studies of lung TRMs in lean
and obese mice. We observe lipid-laden TRMs that express proteins characteristic of immunometabolic
reprogramming and inflammatory activation in the lungs of obese mice. Using minimally biased lipidomics and
in vitro culture techniques, we have identified the fatty acid stearate as a key metabolic signal that may influence
lung TRM inflammatory functions during obesity. Finally, we find that obesity and stearate cause activation of
the TRM inflammasome—an outcome that is observed in non-lung TRMs during obesity and may contribute to
OAA immunopathology. Based on these data, I hypothesize that stearate activates an immunometabolic
functional program in lung TRMs that causes exaggerated inflammasome-mediated inflammation in response to
innate stimuli. The objectives of this grant are to: (1) identify the lipid signals, cellular metabolic pathways, and
inflammatory consequences of obesity-associated lung TRM immunometabolic reprogramming in mice and
humans and (2) test the contribution of the TRM inflammasome to OAA-like innate lung inflammation. To attain
these objectives, we have developed or obtained novel mouse model systems and established unique
collaborations that will allow us to mechanistically interrogate obesity-associated immunometabolic
reprogramming of lung TRMs in mice, and translate our observations to pediatric and adult subjects. Doing so
will identify molecules and pathways that can be targeted by future OAA-specific therapeutics, and inform studies
of other obesity-associated inflammatory lung diseases.

## Key facts

- **NIH application ID:** 10753575
- **Project number:** 5R01HL162715-02
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** David Andrew Hill
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $581,456
- **Award type:** 5
- **Project period:** 2022-12-15 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10753575

## Citation

> US National Institutes of Health, RePORTER application 10753575, Impact of Obesity on Lung Macrophage Metabolism and Inflammation (5R01HL162715-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10753575. Licensed CC0.

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