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Adipocyte deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality

Author

Listed:
  • Rongling Wang

    (University of Edinburgh)

  • Mario Gomez Salazar

    (University of Edinburgh)

  • Iris Pruñonosa Cervera

    (University of Edinburgh)

  • Amanda Coutts

    (Clifton)

  • Karen French

    (University of Edinburgh)

  • Marlene Magalhaes Pinto

    (University of Edinburgh)

  • Sabrina Gohlke

    (Potsdam-Rehbrücke)

  • Ruben García-Martín

    (Campus-UAM)

  • Matthias Blüher

    (Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig)

  • Christopher J. Schofield

    (Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research University of Oxford)

  • Ioannis Kourtzelis

    (University of York)

  • Roland H. Stimson

    (University of Edinburgh)

  • Cécile Bénézech

    (University of Edinburgh)

  • Mark Christian

    (Clifton)

  • Tim J. Schulz

    (Potsdam-Rehbrücke
    German Center for Diabetes Research (DZD))

  • Elias F. Gudmundsson

    (Icelandic Heart Association)

  • Lori L. Jennings

    (Novartis Institutes for Biomedical Research)

  • Vilmundur G. Gudnason

    (Icelandic Heart Association
    University of Iceland)

  • Triantafyllos Chavakis

    (University of Edinburgh
    German Center for Diabetes Research (DZD)
    Technische Universität Dresden
    University Hospital and Faculty of Medicine Technische Universität Dresden)

  • Nicholas M. Morton

    (University of Edinburgh
    Clifton)

  • Valur Emilsson

    (Icelandic Heart Association
    University of Iceland)

  • Zoi Michailidou

    (University of Edinburgh
    Clifton)

Abstract

Enhancing thermogenic brown adipose tissue (BAT) function is a promising therapeutic strategy for metabolic disease. However, predominantly thermoneutral modern human living conditions deactivate BAT. We demonstrate that selective adipocyte deficiency of the oxygen-sensor HIF-prolyl hydroxylase (PHD2) gene overcomes BAT dormancy at thermoneutrality. Adipocyte-PHD2-deficient mice maintain higher energy expenditure having greater BAT thermogenic capacity. In human and murine adipocytes, a PHD inhibitor increases Ucp1 levels. In murine brown adipocytes, antagonising the major PHD2 target, hypoxia-inducible factor-(HIF)−2a abolishes Ucp1 that cannot be rescued by PHD inhibition. Mechanistically, PHD2 deficiency leads to HIF2 stabilisation and binding of HIF2 to the Ucp1 promoter, thus enhancing its expression in brown adipocytes. Serum proteomics analysis of 5457 participants in the deeply phenotyped Age, Gene and Environment Study reveal that serum PHD2 associates with increased risk of metabolic disease. Here we show that adipose-PHD2-inhibition is a therapeutic strategy for metabolic disease and identify serum PHD2 as a disease biomarker.

Suggested Citation

  • Rongling Wang & Mario Gomez Salazar & Iris Pruñonosa Cervera & Amanda Coutts & Karen French & Marlene Magalhaes Pinto & Sabrina Gohlke & Ruben García-Martín & Matthias Blüher & Christopher J. Schofiel, 2024. "Adipocyte deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51718-7
    DOI: 10.1038/s41467-024-51718-7
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    References listed on IDEAS

    as
    1. Valur Emilsson & Valborg Gudmundsdottir & Alexander Gudjonsson & Thorarinn Jonmundsson & Brynjolfur G. Jonsson & Mohd A. Karim & Marjan Ilkov & James R. Staley & Elias F. Gudmundsson & Lenore J. Laune, 2022. "Coding and regulatory variants are associated with serum protein levels and disease," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Alexander Gudjonsson & Valborg Gudmundsdottir & Gisli T. Axelsson & Elias F. Gudmundsson & Brynjolfur G. Jonsson & Lenore J. Launer & John R. Lamb & Lori L. Jennings & Thor Aspelund & Valur Emilsson &, 2022. "A genome-wide association study of serum proteins reveals shared loci with common diseases," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    3. Valur Emilsson & Elias F. Gudmundsson & Thorarinn Jonmundsson & Brynjolfur G. Jonsson & Michael Twarog & Valborg Gudmundsdottir & Zhiguang Li & Nancy Finkel & Stephen Poor & Xin Liu & Robert Esterberg, 2022. "A proteogenomic signature of age-related macular degeneration in blood," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
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