# Molecular mechanisms of thermogenesis

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2020 · $436,625

## Abstract

ABSTRACT
Current treatments for obesity fail to significantly impact body weight and protect against its devastating health
consequences. A promising approach to induce weight loss is to increase energy expenditure and nutrient
disposal. However, the incomplete understanding of the mitochondrial mechanisms and physiological factors
that regulate energy expenditure and fuel disposal has hindered progress. Uncoupling protein-3 (UCP3) is a
skeletal muscle-enriched member of the widely conserved class of mitochondrial anion / solute carrier
superfamily of proteins linked in a variety of clinical genetic studies to obesity in prone human populations.
UCP3 activation increases insulin sensitivity, fatty acid oxidation, and thermogenesis, and loss of UCP3
promotes obesity under high caloric load. Targeting UCP3 (and UCP1) for increasing energy expenditure,
while highly promising, has been confounded by (A) the lack of understanding of how it regulates fat oxidation,
(B) how it is regulated at a molecular level, and (C) what it actually transports. Work in this application
addresses each of these gaps in uncoupling protein biology and importantly, significantly delves into how
UCP1 functions as well. We discovered that UCP3 regulates mitochondrial C4 substrate (malate, aspartate)
transport directly (when reconstituted into liposomes and in yeast) and in muscle mitochondria from wild type
but not UCP3 knockout mice. Further we have identified two UCP3 transport-defective mutants that will be
critical for work in this application. We also found that UCP3 forms a complex with mitochondrial malate
dehydrogenase (MDH2), which converts malate to oxaloacetate, the mitochondrial metabolite necessary for
complete fatty acid oxidation. Finally, we show that skeletal muscle-specific UCP3 expression rescues drug-
induced thermogenesis (a response that requires fatty acids) in global UCP3 knockout mice, showing that
muscle may be a novel site of UCP3 thermogenesis. The overall working hypothesis of this proposal is that
UCP3 coordinates the maximal capacity for skeletal muscle thermogenesis and fat oxidation through the control
of mitochondrial malate and potentially other C4 metabolite mitochondrial import (anaplerotic flux of malate and
likely aspartate, among others). We will test this in the following Aims: (1) Define the role of UCP3 in C4
metabolite mitochondrial transport and the molecular mechanisms involved. (2) Examine the mechanisms and
physiological relevancy of UCP3-dependent metabolite transport for fat oxidation and UCP3-mediated
metabolite transport in muscle in vivo using state of the art metabolic tracer experiments. Significance
summary: This work will provide fundamental and novel insights into the molecular mechanisms regulating UCP3
(and likely UCP1), and will identify novel UCP-modulating “druggable” targets and mechanisms.

## Key facts

- **NIH application ID:** 10126288
- **Project number:** 2R01DK089224-06A1
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** John DiGiovanni
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $436,625
- **Award type:** 2
- **Project period:** 2011-05-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10126288

## Citation

> US National Institutes of Health, RePORTER application 10126288, Molecular mechanisms of thermogenesis (2R01DK089224-06A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10126288. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*