# Hepatic mitochondrial function control of high-fat diet-induced weight gain

> **NIH NIH K01** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2021 · $79,110

## Abstract

PROJECT SUMMARY
Obesity is the strongest independent predictor for the onset and progression of metabolic diseases, such as type
2 diabetes and cardiovascular disease. Weight gain occurs due to a shift to a positive energy balance through
some combination of increased food/energy intake and decreased total energy expenditure. Energy balance is
not constant or consistent, and therefore long-term weight gain occurs as a sum of numerous, small positive
fluctuations over time scales ranging from days to seasons. These acute episodes of positive energy balance
occur as a complex interaction of the current obesogenic environment and inappropriate metabolic regulation.
One route of metabolic regulation may be the control of food/energy intake through a liver/brain axis. The main
goal of the proposed 5-year research career development plan is to facilitate the applicant's transition
from postdoctoral fellow to a fully independent academic scientist. This will be accomplished by training
the applicant in a variety of metabolic, neurophysiology, and molecular techniques that will be used to
identify mechanisms by which the hepatic mitochondrial function impacts short-term, western diet-
induced weight gain. Reduced liver fatty acid oxidation and lower hepatic energy status results in increased
food intake, which requires intact vagal nerve communication between the brain and the liver. Additionally, we
have shown that increased food/energy intake, weight gain, and adiposity are associated with decreased hepatic
fatty acid oxidation and mitochondrial respiratory capacity during a 3-day high fat diet (HFD). The central
hypothesis of this proposal is that reduced hepatic mitochondrial function results in increased acute HFD-induced
weight gain via: 1) increased HFD food intake, and 2) decreased hepatic and systemic utilization of fat. In this
proposal, we will use a liver-specific, PGC-1α heterozygous (LPGC1a+/-) mouse model to study the role of
reduced hepatic mitochondrial respiratory function on HFD-induced weight gain. Hepatic vagotomy will be used
to test the involvement of liver/brain afferent signals in LPGC1a+/- and wildtype mice. Additional work will include
experiments to study the role of hepatic mitochondrial function in onset of metabolic inflexibility and control of
systemic substrate utilization, and the role of liver adenine nucleotide levels in the initiation of hepatic efferent
vagal signal.

## Key facts

- **NIH application ID:** 10450906
- **Project number:** 3K01DK112967-05S1
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** E Matthew Morris
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $79,110
- **Award type:** 3
- **Project period:** 2017-09-08 → 2023-03-07

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450906

## Citation

> US National Institutes of Health, RePORTER application 10450906, Hepatic mitochondrial function control of high-fat diet-induced weight gain (3K01DK112967-05S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10450906. Licensed CC0.

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