# Obesity, Metabolic Syndrome and Asthma

> **NIH NIH R21** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $198,750

## Abstract

Allergic asthma, a disease that affects over 300 million people worldwide, is typically driven by Th2-dominated
immune responses to environmental antigens. Obesity, a disorder afflicting 500 million people worldwide, is
associated with chronic inflammation, elevated proinflammatory cytokine production, and metabolic dysfunction
leading to the development of diabetes, cardiovascular disease, non-alcoholic fatty liver disease and various
cancers. Recent evidence suggests the existence of several asthma “endotypes”– disease subtypes driven by
unique underlying pathogenic mechanisms. The “obese asthma” endotype is associated with: (1) a shift away
from Th2-dominated inflammation towards a more proinflammatory phenotype; (2) a reduction in therapeutic
efficacy of steroids; and (3) a clear female bias in prevalence. While there is consensus regarding these clinical
parameters, identification of underlying mechanisms of “obese asthma” has been hampered by the absence of
a combined model of severe obesity and asthma in female mice. Although reproducible modeling of asthma is
achieved in both male and female mice, modeling of obesity and metabolic dysfunction is largely limited to
male mice. This is largely in part due to poor tractability of obesity and metabolic dysfunction in female mice.
Our novel data demonstrate that housing female mice in temperatures close to their thermoneutral zone (the
temperature at which they are in metabolic homeostasis – 30-33°C) with concomitant HFD feeding promotes
development of severe obesity, adiposity and metabolic dysfunction comparable to that observed in male mice.
Thus, we are now able to simultaneously assess the influence of obesity, adiposity, metabolic dysfunction, and
sex on asthma pathogenesis. In this application, our two independent, yet related, Specific Aims seek to
validate the ability of our novel model to recapitulate three frequent observations in obese asthmatics: (1) the
shift towards a proinflammatory profile; (2) reduced efficacy of steroids; and (3) female preponderance.
Specific Aim 1: Determine if severely obese female mice with metabolic dysfunction develop asthma
comparable to the “obese asthma” endotype described in obese women. Using HFD- or control chow
diet-fed male and female mice, housed at either standard (22°C) or thermoneutral (30-33°C) conditions, we will
induce experimental asthma in a model of robust obesity and metabolic dysfunction. Features of experimental
asthma will be correlated with weight gain, adiposity, parameters of metabolic dysfunction, in a sex-dependent
manner. Specific Aim 2: Determine if obesity and metabolic dysfunction associate with development of
steroid refractory asthma in female mice. The ability of inhaled and systemic steroids to inhibit experimental
asthma and metabolic dysfunction will be assessed in HDM-challenged, HFD- or control diet-fed, TS- and TN-
housed male and female mice. A better understanding of the pathogenesis of the “obese asthma” endoty...

## Key facts

- **NIH application ID:** 10075878
- **Project number:** 5R21AI139829-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Senad Divanovic
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $198,750
- **Award type:** 5
- **Project period:** 2019-12-20 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10075878

## Citation

> US National Institutes of Health, RePORTER application 10075878, Obesity, Metabolic Syndrome and Asthma (5R21AI139829-02). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10075878. Licensed CC0.

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