# Ketone Body Supplementation in Obese Asthma

> **NIH NIH R01** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2021 · $445,631

## Abstract

ABSTRACT
Obesity-associated asthma is increasingly prevalent and presents as severe disease that is very difficult to
treat. Obese asthma exists as phenotypes termed “inherent” (a consequence of weight) and “allergic” (made
worse by obesity), both of which can be effectively modeled in mice. Oxidative stress is increased in obese
asthmatics and may be a target for therapeutic intervention. While weight loss and its associated mobilization
of fatty acids from adipose tissue has salutary effects on symptoms and objective disease, lifestyle alterations,
bariatric surgery, and biological therapeutics have issues including poor long-term compliance, a lack of
desirability, and high cost that limit their success as treatments for obese asthma. During weight loss, fatty
acids mobilized from adipose tissue are subsequently catabolized in the liver to the ketone bodies
acetoacetate (AcAc) and β-hydroxybutyrate (BHB). Ketone bodies function as antioxidants, provide an energy
source that makes cells less reliant on glycolysis, and exert anti-inflammatory effects. Based on our published
and preliminary data, we hypothesize that therapeutic augmentation of ketone body concentrations in the
circulation will elicit improvements in obese inherent and allergic asthma through decreasing cellular redox
stress and inhibiting pro-inflammatory cytokine production. In SA1, to ascertain whether and which ketone
bodies afford protection against the major aspects of obese inherent asthma, we will employ mouse models of
diet-induced obesity and two genetic models of obesity accompanied by dietary or pharmacological
augmentation of circulating ketone bodies accomplished by feeding a low-fat diet or a ketogenic diet, or
administration of ketone bodies (BHB and AcAc), an agent that promotes ketone body formation (1,3-
butanediol), or ketone ester. Measured outcomes include methacholine responsiveness, airway inflammation,
lung histology, serum cytokines, and immunophenotyping. In SA2, to evaluate the impact of in vivo ketone
body modulation on the pathophysiological manifestations of obese allergic asthma, we will expose the diet- or
genetically-induced mouse obesity models to chronic inhalational house dust mite allergen exposure
accompanied by dietary or pharmacological augmentation of circulating ketone bodies during the asthma
exacerbation phase. Outcomes to be measured include methacholine responsiveness, airway inflammation,
immunophenotyping, and lung remodeling. In SA3, to investigate the mechanisms of ketone body actions, we
will stimulate primary airway epithelial cell and leukocyte cultures from lean and obese, non-allergic and HDM-
allergic mice, in the absence and presence of ketone bodies in vitro, as well as examine tissues and cells from
mice treated in SA1 and SA2. We will assess whether the intrinsic differences in cytokine secretion, glycolysis,
mitochondrial oxidative stress, and endoplasmic reticulum stress between cells from lean and obese mice are
modul...

## Key facts

- **NIH application ID:** 10125190
- **Project number:** 5R01HL142081-04
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** Matthew E Poynter
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $445,631
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10125190

## Citation

> US National Institutes of Health, RePORTER application 10125190, Ketone Body Supplementation in Obese Asthma (5R01HL142081-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10125190. Licensed CC0.

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