2. Academic Validation
  3. Adipocyte deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality

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

  • Nat Commun. 2024 Aug 29;15(1):7483. doi: 10.1038/s41467-024-51718-7.
Rongling Wang 1,  Mario Gomez Salazar 1,  Iris Pruñonosa Cervera 1,  Amanda Coutts 2,  Karen French 1,  Marlene Magalhaes Pinto 1,  Sabrina Gohlke 3,  Ruben García-Martín 4,  Matthias Blüher 5,  Christopher J Schofield 6,  Ioannis Kourtzelis 7,  Roland H Stimson 1,  Cécile Bénézech 1,  Mark Christian 2,  Tim J Schulz 3 8,  Elias F Gudmundsson 9,  Lori L Jennings 10,  Vilmundur G Gudnason 9 11,  Triantafyllos Chavakis 1 8 12 13,  Nicholas M Morton 1 2,  Valur Emilsson 9 11,  Zoi Michailidou 14 15
Affiliations

Affiliations

  • 1 Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
  • 2 Department of Biosciences, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham, UK.
  • 3 Department of Adipocyte Development and Nutrition, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany.
  • 4 Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC (CNB-CSIC), Campus-UAM, Madrid, Spain.
  • 5 Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany.
  • 6 Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research University of Oxford, Oxford, UK.
  • 7 Hull York Medical School, York Biomedical Research Institute, University of York, York, UK.
  • 8 German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
  • 9 Icelandic Heart Association, Kopavogur, Iceland.
  • 10 Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • 11 Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
  • 12 Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
  • 13 Paul Langerhans Institute Dresden, Helmholtz Zentrum München, University Hospital and Faculty of Medicine Technische Universität Dresden, Dresden, Germany.
  • 14 Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK. zoi.michailidou@ntu.ac.uk.
  • 15 Department of Biosciences, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham, UK. zoi.michailidou@ntu.ac.uk.
PMID: 39209825 DOI: 10.1038/s41467-024-51718-7
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.

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