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The scaffold protein p62 regulates adaptive thermogenesis through ATF2 nuclear target activation

Author

Listed:
  • Katrin Fischer

    (Helmholtz Zentrum München and German National Diabetes Center (DZD))

  • Anna Fenzl

    (Helmholtz Zentrum München and German National Diabetes Center (DZD))

  • Dianxin Liu

    (Vanderbilt University Medical Center)

  • Kenneth A. Dyar

    (Helmholtz Zentrum München and German National Diabetes Center (DZD))

  • Maximilian Kleinert

    (Helmholtz Zentrum München and German National Diabetes Center (DZD)
    Technische Universität München
    University of Copenhagen)

  • Markus Brielmeier

    (Research Unit Comparative Medicine, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH)

  • Christoffer Clemmensen

    (Helmholtz Zentrum München and German National Diabetes Center (DZD)
    University of Copenhagen)

  • Anna Fedl

    (Helmholtz Zentrum München and German National Diabetes Center (DZD))

  • Brian Finan

    (Helmholtz Zentrum München and German National Diabetes Center (DZD)
    Novo Nordisk Research Center)

  • Andre Gessner

    (University Hospital Regensburg)

  • Martin Jastroch

    (Helmholtz Zentrum München and German National Diabetes Center (DZD)
    The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University)

  • Jianfeng Huang

    (Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute)

  • Susanne Keipert

    (Helmholtz Zentrum München and German National Diabetes Center (DZD)
    The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University)

  • Martin Klingenspor

    (Chair of Molecular Nutritional Medicine, Technical University of Munich, TUM School of Life Sciences Weihenstephan
    EKFZ—Else-Kröner Fresenius Center for Nutritional Medicine, Technical University of Munich)

  • Jens C. Brüning

    (Max Planck Institute for Metabolism Research
    University Hospital Cologne
    University of Cologne)

  • Manfred Kneilling

    (Eberhard Karls University Tübingen
    Eberhard Karls University Tübingen)

  • Florian C. Maier

    (Eberhard Karls University Tübingen)

  • Ahmed E. Othman

    (Eberhard Karls University Hospital Tübingen)

  • Bernd J. Pichler

    (Eberhard Karls University Tübingen)

  • Ines Pramme-Steinwachs

    (Helmholtz Zentrum München and German National Diabetes Center (DZD))

  • Stephan Sachs

    (Helmholtz Zentrum München and German National Diabetes Center (DZD))

  • Angelika Scheideler

    (Research Unit Comparative Medicine, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH)

  • Wolfgang M. Thaiss

    (Eberhard Karls University Tübingen
    Eberhard Karls University Hospital Tübingen)

  • Henriette Uhlenhaut

    (Helmholtz Zentrum München and German National Diabetes Center (DZD))

  • Siegfried Ussar

    (Helmholtz Zentrum München and German National Diabetes Center (DZD))

  • Stephen C. Woods

    (University of Cincinnati)

  • Julia Zorn

    (University of Copenhagen)

  • Kerstin Stemmer

    (Helmholtz Zentrum München and German National Diabetes Center (DZD)
    University of Konstanz)

  • Sheila Collins

    (Vanderbilt University Medical Center)

  • Maria Diaz-Meco

    (Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute)

  • Jorge Moscat

    (Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute)

  • Matthias H. Tschöp

    (Helmholtz Zentrum München and German National Diabetes Center (DZD)
    Technische Universität München)

  • Timo D. Müller

    (Helmholtz Zentrum München and German National Diabetes Center (DZD)
    Eberhard Karls University Hospitals and Clinics)

Abstract

During β-adrenergic stimulation of brown adipose tissue (BAT), p38 phosphorylates the activating transcription factor 2 (ATF2) which then translocates to the nucleus to activate the expression of Ucp1 and Pgc-1α. The mechanisms underlying ATF2 target activation are unknown. Here we demonstrate that p62 (Sqstm1) binds to ATF2 to orchestrate activation of the Ucp1 enhancer and Pgc-1α promoter. P62Δ69-251 mice show reduced expression of Ucp1 and Pgc-1α with impaired ATF2 genomic binding. Modulation of Ucp1 and Pgc-1α expression through p62 regulation of ATF2 signaling is demonstrated in vitro and in vivo in p62Δ69-251 mice, global p62−/− and Ucp1-Cre p62flx/flx mice. BAT dysfunction resulting from p62 deficiency is manifest after birth and obesity subsequently develops despite normal food intake, intestinal nutrient absorption and locomotor activity. In summary, our data identify p62 as a master regulator of BAT function in that it controls the Ucp1 pathway through regulation of ATF2 genomic binding.

Suggested Citation

  • Katrin Fischer & Anna Fenzl & Dianxin Liu & Kenneth A. Dyar & Maximilian Kleinert & Markus Brielmeier & Christoffer Clemmensen & Anna Fedl & Brian Finan & Andre Gessner & Martin Jastroch & Jianfeng Hu, 2020. "The scaffold protein p62 regulates adaptive thermogenesis through ATF2 nuclear target activation," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16230-8
    DOI: 10.1038/s41467-020-16230-8
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    Cited by:

    1. Leslie A. Rowland & Adilson Guilherme & Felipe Henriques & Chloe DiMarzio & Sean Munroe & Nicole Wetoska & Mark Kelly & Keith Reddig & Gregory Hendricks & Meixia Pan & Xianlin Han & Olga R. Ilkayeva &, 2023. "De novo lipogenesis fuels adipocyte autophagosome and lysosome membrane dynamics," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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