1. Biochemistry and Chemical Biology
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OPA1 deletion in brown adipose tissue Improves thermoregulation and systemic metabolism via FGF21

Research Article
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Cite this article as: eLife 2021;10:e66519 doi: 10.7554/eLife.66519

Abstract

Adrenergic stimulation of brown adipocytes alters mitochondrial dynamics, including the mitochondrial fusion protein optic atrophy 1 (OPA1). However, direct mechanisms linking OPA1 to brown adipose tissue (BAT) physiology are incompletely understood. We utilized a mouse model of selective OPA1 deletion in BAT (OPA1 BAT KO) to investigate the role of OPA1 in thermogenesis. OPA1 is required for cold-induced activation of thermogenic genes in BAT. Unexpectedly, OPA1 deficiency induced fibroblast growth factor 21 (FGF21) as a BATokine in an activating transcription factor 4 (ATF4)-dependent manner. BAT-derived FGF21 mediates an adaptive response, by inducing browning of white adipose tissue, increasing resting metabolic rates, and improving thermoregulation. However, mechanisms independent of FGF21, but dependent on ATF4 induction, promote resistance to diet-induced obesity in OPA1 BAT KO mice. These findings uncover a homeostatic mechanism of BAT-mediated metabolic protection governed in part by an ATF4-FGF21 axis, that is activated independently of BAT thermogenic function.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for all figures.

Article and author information

Author details

  1. Renata O Pereira

    Internal Medicine, University of Iowa, Iowa City, United States
    For correspondence
    renata-pereira@uiowa.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5809-4669
  2. Alex Marti

    Internal Medicine, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Angela Crystal Olvera

    Internal Medicine, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Satya Murthy Tadinada

    Internal Medicine, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Sarah Hartwick Bjorkman

    Obstetrics and Gynecology, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Eric Thomas Weatherford

    Internal Medicine, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Donald A Morgan

    Neuroscience and Pharmacology, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Michael Westphal

    Internal Medicine, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Pooja H Patel

    Internal Medicine, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5345-0158
  10. Ana Karina Kirby

    Internal Medicine, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Rana Hewezi

    Internal Medicine, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. William Bùi Trần

    Internal Medicine, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Luis Miguel García-Peña

    Internal Medicine, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8718-6490
  14. Rhonda A Souvenir

    Internal Medicine, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8880-2483
  15. Monika Mittal

    Internal Medicine, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Christopher M Adams

    Department of Internal Medicine, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Kamal Rahmouni

    Pharmacology, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Matthew J Potthoff

    Pharmacology, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. E Dale Abel

    Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5290-0738

Funding

National Institutes of Health (HL127764)

  • E Dale Abel

National Institutes of Health (HL112413)

  • E Dale Abel

American Heart Association (20SFRN35120123)

  • E Dale Abel

American Heart Association (15SDG25710438)

  • Renata O Pereira

National Institutes of Health (DK125405)

  • Renata O Pereira

National Institutes of Health (T32DK112751)

  • Sarah Hartwick Bjorkman

National Institutes of Health (1R25GM116686)

  • Luis Miguel García-Peña

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 (#8051408 and 0032294) of the University of Iowa.

Reviewing Editor

  1. Joel K Elmquist, University of Texas Southwestern Medical Center, United States

Publication history

  1. Received: January 13, 2021
  2. Accepted: May 2, 2021
  3. Accepted Manuscript published: May 4, 2021 (version 1)
  4. Version of Record published: May 17, 2021 (version 2)

Copyright

© 2021, Pereira 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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