Mitochondrial pyruvate carrier is required for optimal brown fat thermogenesis
- University of Utah, United States
- The University of Texas Southwestern Medical Center, United States
- University of California, Los Angeles, United States
Abstract
Brown adipose tissue (BAT) is composed of thermogenic cells that convert chemical energy into heat to help maintain a constant body temperature and counteract metabolic disease in mammals. The metabolic adaptations required for thermogenesis are not fully understood. Here we explore how steady state levels of metabolic intermediates are altered in brown adipose tissue in response to cold exposure. Transcriptome and metabolome analysis revealed changes in pathways involved in amino acid, glucose, and TCA cycle metabolism. Using isotopic labeling experiments, we found that activated brown adipocytes increased labeling of pyruvate and TCA cycle intermediates from U13C-glucose. Although glucose oxidation has been implicated as being essential for thermogenesis, its requirement for efficient thermogenesis has not been directly tested. Here we show that mitochondrial pyruvate uptake is essential for optimal thermogenesis, as conditional deletion of Mpc1 in brown adipocytes leads to impaired cold adaptation. Isotopic labeling experiments using U13C-glucose showed that loss of MPC1 led to impaired labeling of TCA cycle intermediates, while labeling of glycolytic intermediates was unchanged. Loss of MPC1 in BAT increased 3-hydroxybutyrate levels in blood and BAT in response to the cold, suggesting that ketogenesis provides an alternative fuel source to compensate for impaired mitochondrial oxidation of cytosolic pyruvate. Collectively, these studies highlight that complete glucose oxidation is essential for optimal brown fat thermogenesis.
Data availability
RNA sequencing data will be deposited in GEO under accession codes GSE135391.
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Brown fat room temperature and coldNCBI Gene Expression Omnibus, GSE135391.
Article and author information
Author details
Claudio J Villanueva
Funding
National Institutes of Health (1R01DK103930)
- Claudio J Villanueva
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#18-08004) of the University of Utah. The protocol was approved by the Committee on the Ethics of Animal Experiments of the University of Utah.
Reviewing Editor
- Michael Czech, University of Massachusetts Medical School, United States
Publication history
- Received: October 8, 2019
- Accepted: August 13, 2020
- Accepted Manuscript published: August 14, 2020 (version 1)
- Version of Record published: September 7, 2020 (version 2)
Copyright
© 2020, Panic et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Mitochondrial pyruvate carrier is required for optimal brown fat thermogenesis
eLife 9:e52558.
https://doi.org/10.7554/eLife.52558
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