# The role of ketogenic diet metabolites in molecular signaling within distinct brain cell populations.

> **NIH NIH F30** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2020 · $50,520

## Abstract

Project Summary
 The brain exhibits considerable energy demand and consumes as much as 20% of total caloric intake.
Primarily, the adult brain acquires the vast majority of its energy through the breakdown of carbohydrates. The
capacity to utilize carbohydrates as an energy source is reduced during brain aging and in the Alzheimer's
disease (AD) afflicted brain as evidenced by FDG-PET studies. This decline in carbohydrate utilization is an
early preclinical change in AD and may be a viable therapeutic target to slow or prevent disease progression.
This shortfall may be corrected by substituting an alternative energy source for the brain. The brain will readily
catabolize ketone bodies for energy production in certain circumstances. Typically, ketone bodies are only
produced in the adult human during periods of sustained caloric restriction or when maintained on a diet high in
fat and low in carbohydrate content. These so-called ketogenic diets have been in use for nearly a century in
the clinic for the treatment of intractable epilepsy. Additionally, a randomized control trial has demonstrated
some efficacy for the ketogenic diet in improving cognitive performance in patients with AD. While the
ketogenic diet has neurologic benefit in humans, its mechanism of action remains poorly understood. The
present proposal seeks to explain how the ketogenic diet and its primary metabolites, fats and ketone bodies,
influence molecular signaling pathways in the central nervous system in distinct brain cell populations.
 We hypothesize that neurons preferentially utilize ketone bodies as an energy source and spare fats
with the reverse being true of astrocytes. We further hypothesize that these metabolites further influence
intracellular signaling pathways by altering bioenergetic flux and gene transcription. For our first aim, we plan
to assess how primary nervous system cell lines respond bioenergetically to the presence of fatty acids and
ketone bodies. This aim will be tested in vitro through primary cultures of neurons and astrocytes generated
from embryonic rat forebrain and in vivo through the isolation of distinct cell types from adult mouse brain using
FACS technology. Our second aim will make use of a transgenic mouse line exhibiting constitutive ketogenesis
in the absence of dietary manipulation to examine the effects of sustained brain ketone delivery. This approach
will allow us to examine the in vivo effects of ketone bodies on the brain without creating confounding variables
introduced by the use of the ketogenic diet. The broad, long-term objective of this research is to further
elucidate how the brain utilizes bioenergetics substrates in specific brain cell populations. This includes
defining the mechanism of benefit of ketogenic therapies in AD and epilepsy to better target novel molecular
pathways in the treatment of these pathologies and improve patient lives.

## Key facts

- **NIH application ID:** 9962243
- **Project number:** 5F30AG058397-03
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** Scott Joshua Koppel
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-07-07

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962243

## Citation

> US National Institutes of Health, RePORTER application 9962243, The role of ketogenic diet metabolites in molecular signaling within distinct brain cell populations. (5F30AG058397-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9962243. Licensed CC0.

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