# Metabolic Link Between Peroxisomes and Mitochondria in the Regulation of Thermogenesis

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $393,750

## Abstract

Project summary
Peroxisomes carry out many key functions related to ROS and lipid metabolism, including oxidation of very
long chain fatty acids and synthesis of ether lipids. As highly plastic organelles, peroxisomes can modify their
size, morphology, abundance, and function, depending on external stimuli. Our preliminary studies suggest
that peroxisomal biogenesis increases in adipose tissue in response to cold exposure, in a manner dependent
on the thermogenic transcription factor PRDM16, consistent with the possibility that peroxisomes are involved
in thermogenesis. Using a new mouse model of adipose-specific peroxisome deficiency, we discovered that
peroxisomes are critical for brown fat-mediated thermogenesis and that the loss of peroxisomes in adipose
tissue is associated with decreased energy expenditure and increased adiposity. By pursuing the molecular
mechanism through which peroxisomes regulate adipose tissue thermogenesis, our preliminary studies
implicate peroxisomes in mitochondrial division. As dynamic organelles, mitochondria undergo repeated cycles
of fission and fusion. Combined with the cold-induced stimulation of lipolysis, activation of mitochondrial fission
is thought to serve as a critical physiological regulator of energy expenditure and thermogenic function of
brown fat. Our studies suggest that the loss of peroxisomes impairs cold-induced mitochondrial fission and
decreases mitochondrial DNA content in BAT.
These phenotypes do not appear to be related to impaired ability of peroxisomes to oxidize very long chain
fatty acids or through an altered redox state in brown adipocytes in the absence of peroxisomes. Instead, our
results implicate the ability of peroxisomes to synthesize a type of ether lipids called plasmalogens in the
mechanism. Plasmalogens are present in the mitochondrial membrane and inhibition of their synthesis in
brown adipocytes mimics the effect of blocking peroxisomal biogenesis on mitochondrial morphology. These
data lead us to hypothesize that peroxisomes regulate adipose tissue thermogenesis by channeling
plasmalogens to mitochondria to mediate mitochondrial fission. We propose two specific aims to test this
hypothesis. In Aim 1, we will elucidate the molecular mechanism through which peroxisomes regulate
mitochondrial dynamics and adipose tissue thermogenesis. The second Aim will study the role of peroxisomal
lipid synthesis in mitochondrial function, thermogenesis, and metabolic homeostasis using mice with adipose-
specific inactivation of plasmalogen synthesis. Together, this work will provide a significant mechanistic insight
into the role of peroxisomes in adipose tissue thermogenesis. Understanding how peroxisomes regulate
mitochondrial fission could lead to novel strategies to exploit the thermogenic function of brown fat for
treatment of obesity and diabetes.

## Key facts

- **NIH application ID:** 10130507
- **Project number:** 5R01DK118333-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Irfan J Lodhi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $393,750
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10130507

## Citation

> US National Institutes of Health, RePORTER application 10130507, Metabolic Link Between Peroxisomes and Mitochondria in the Regulation of Thermogenesis (5R01DK118333-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10130507. Licensed CC0.

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