# Role of Muscle Ketone Metabolism in Mediating the Metabolic Benefits of Weight Loss

> **NIH NIH K01** · DUKE UNIVERSITY · 2021 · $110,835

## Abstract

PROJECT SUMMARY
Dietary regimens that promote ketone production are gaining popularity due to their ability to facilitate weight
loss and improve metabolic health. Ketones (e.g. acetoacetate and 3-hydroxybutyrate (3OHB)) are produced by
the liver and oxidized by the brain and peripheral tissues when glucose is low. Whereas the field has largely
focused on the positive effects of ketones on the brain and heart, the role of ketone oxidation in skeletal muscle
has been largely overlooked and under investigated. Data from our laboratory suggests that the skeletal muscle
is a major site of 3OHB clearance, therefore we postulate that skeletal muscle 3OHB oxidation is necessary for
optimal metabolic benefits of ‘ketogenic’ dietary weight loss regimens. To this end, this application links the
enzyme that catalyzes the first step of 3OHB oxidation, D-ꞵ-hydroxybutyrate dehydrogenase (BDH1), to
improved whole-body glucose metabolism and energy homeostasis due to post-obesity weight loss. The central
objective of this proposal is to determine if skeletal muscle BDH1 plays a key role in mediating the health
benefits of dietary regimens that promote ketogenesis and weight loss. BDH1 catalyzes a near-equilibrium
reaction that couples ketone oxidation to the mitochondrial NAD(H) redox state. Herein, we propose a novel
conceptual model that positions BDH1 as a mitochondrial redox buffer that promotes optimal skeletal muscle
health during fasting and refeeding. Our conceptual model and central objective will be rigorously tested by the
following studies. First, we use a novel mouse model with an inducible skeletal muscle-specific deletion of BDH1
to determine the impact of BDH1 on skeletal muscle mitochondrial bioenergetics and glucose metabolism in
response to fasting and refeeding. Second, we will test the hypothesis that muscle BDH1 is required for the
metabolic benefits of calorie-restricted feeding of a typical Western diet. Third, we will apply genetic engineering
in primary human skeletal muscle cells test the hypothesis that ketone-induced shifts in the myocellular redox
state impact glucose uptake and downstream metabolism. Results from these studies will expand our
understanding of the functional relevance of skeletal muscle BDH1 and ketone oxidation with the long term goal
of identifying new therapeutic targets for the prevention of obesity-induced metabolic disease. Importantly, this
project will provide advanced training and mentoring in ketone metabolism, cellular genetic engineering, 13C
stable isotope tracing, and computational 13C metabolic flux analysis. The career development plan will be
implemented via a team of outstanding mentors including Dr. Muoio (Duke Molecular Physiology Institute, DMPI)
as the primary mentor, Dr. Newgard (DMPI) as the co-mentor, and Drs. Zhang (DMPI) and Crawford (UMN) as
members of the advisory committee. The DMPI is an ideal environment for training as it contains a diverse team
of researchers with expertise in nutri...

## Key facts

- **NIH application ID:** 10245167
- **Project number:** 5K01DK125609-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Ashley Silberman Williams
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $110,835
- **Award type:** 5
- **Project period:** 2020-09-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10245167

## Citation

> US National Institutes of Health, RePORTER application 10245167, Role of Muscle Ketone Metabolism in Mediating the Metabolic Benefits of Weight Loss (5K01DK125609-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10245167. Licensed CC0.

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