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

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

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August 29, 2024

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.