Mitochondrial pyruvate carrier is required for optimal brown fat thermogenesis

  1. Vanja Panic
  2. Stephanie Pearson
  3. James Banks
  4. Trevor S Tippetts
  5. Jesse N Velasco-Silva
  6. Sanghoon Lee
  7. Judith Simcox
  8. Gisela Geoghegan
  9. Claire L Bensard
  10. Tyler van Ry
  11. Will L Holland
  12. Scott A Summers
  13. James Cox
  14. Gregory S Ducker
  15. Jared Rutter
  16. Claudio J Villanueva  Is a corresponding author
  1. University of Utah, United States
  2. The University of Texas Southwestern Medical Center, United States
  3. 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.

The following data sets were generated

Article and author information

Author details

  1. Vanja Panic

    Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Stephanie Pearson

    Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. James Banks

    Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Trevor S Tippetts

    Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1419-7057
  5. Jesse N Velasco-Silva

    Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Sanghoon Lee

    Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Judith Simcox

    Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Gisela Geoghegan

    Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Claire L Bensard

    Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Tyler van Ry

    Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Will L Holland

    Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Scott A Summers

    Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. James Cox

    Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Gregory S Ducker

    Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Jared Rutter

    Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2710-9765
  16. Claudio J Villanueva

    Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, United States
    For correspondence
    cvillanueva@ucla.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9731-7463

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.

Reviewing Editor

  1. Michael Czech, University of Massachusetts Medical School, United States

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.

Version history

  1. Received: October 8, 2019
  2. Accepted: August 13, 2020
  3. Accepted Manuscript published: August 14, 2020 (version 1)
  4. 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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  1. Vanja Panic
  2. Stephanie Pearson
  3. James Banks
  4. Trevor S Tippetts
  5. Jesse N Velasco-Silva
  6. Sanghoon Lee
  7. Judith Simcox
  8. Gisela Geoghegan
  9. Claire L Bensard
  10. Tyler van Ry
  11. Will L Holland
  12. Scott A Summers
  13. James Cox
  14. Gregory S Ducker
  15. Jared Rutter
  16. Claudio J Villanueva
(2020)
Mitochondrial pyruvate carrier is required for optimal brown fat thermogenesis
eLife 9:e52558.
https://doi.org/10.7554/eLife.52558

Share this article

https://doi.org/10.7554/eLife.52558

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