# Divergence in Aerobic Capacity Drives Liver and Brain Health

> **NIH NIH R01** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2021 · $377,622

## Abstract

Project Abstract/Summary
Alzheimer’s Disease (AD) is the most common form of dementia evoking a terrible personal and financial toll.
Most AD cases are sporadic with no known direct genetic cause. Several factors associate strongly with AD
risk including metabolic disease states of two diabetes (T2D) and more recently fatty liver disease. A physical
trait, aerobic capacity, the maximal capacity to use oxygen during exercise, has been independently linked to
increased risk for T2D, fatty liver, and AD. How intrinsic aerobic capacity impacts disease independent of daily
activity or exercise remains relatively unknown. We use rats selectively bred for divergence in intrinsic aerobic
capacity to reveal mechanisms. Two-way artificial selective breeding created high and low capacity runner
(HCR/LCR) rat strains divergent for intrinsic aerobic capacity. HCR/LCR rats are not exposed to exercise and
display a contrasting, 40% difference in intrinsic aerobic capacity in a sedentary condition. LCR are highly
susceptible to high fat diet (HFD)-induced obesity, hepatic steatosis, insulin resistance, neurodegeneration,
and a shorter lifespan (4-6 months). In contrast, the HCR are resistant to HFD induced steatosis, insulin
resistance and obesity. This polygenetic model more accurately reflects the impact of intrinsic aerobic capacity
on human health and mortality, and better represents the protection or susceptibility for clinical development of
many chronic diseases such as T2D, hepatic steatosis, and AD compared to other animal models. Our parent
grant (R01DK121497) investigates intrinsic aerobic capacity and exercise in mediating the risk of hepatic
steatosis through liver mitochondrial function/bile acid synthesis and epigenetic/proteomic modulations. We
recently examined brain samples from HCR/LCR rats and found increased phosphorylated tau, amyloid beta
(Aβ) (both are AD pathological hallmarks) and altered mitochondrial function. Importantly, HCR/LCR rats are
not transgenic models of AD; but a polygenetic model which more faithfully represents the clinical links
between aerobic capacity, exercise, and chronic disease. We propose to examine the brains from HCR/LCR
rats and sedentary/exercised mice fed a HFD in conjunction with the parent R01. We will also examine the
effects of liver derived excretions (metabolites, hormones, proteins) on neuronal and glial cell health and
function. We will have the ability to correlate liver health, systemic anthropometrics, and aerobic capacity. The
work proposed here is a natural extension of our ongoing research and will further the AD field by establishing
mechanistic links between aerobic capacity, liver health, and AD. The experiments we now propose are well-
within the scope of NOT-AG-20-034.

## Key facts

- **NIH application ID:** 10286535
- **Project number:** 3R01DK121497-03S1
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** John P Thyfault
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $377,622
- **Award type:** 3
- **Project period:** 2019-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10286535

## Citation

> US National Institutes of Health, RePORTER application 10286535, Divergence in Aerobic Capacity Drives Liver and Brain Health (3R01DK121497-03S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10286535. Licensed CC0.

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