Adipocyte deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality
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.
Authors
- Vilmundur Guðnason (ORCID: https://orcid.org/0000-0001-5696-0084)
- Zoi Michailidou (ORCID: https://orcid.org/0000-0003-0085-4842)
- Lori L. Jennings (ORCID: https://orcid.org/0000-0001-5130-8417)
- Marlene Magalhaes Pinto
- Rongling Wang (ORCID: https://orcid.org/0000-0001-8719-938X)
- Roland H. Stimson (ORCID: https://orcid.org/0000-0002-9002-6188)
- Karen L. French
- Nicholas Morton (ORCID: https://orcid.org/0000-0003-0003-4182)
- Mark Christian (ORCID: https://orcid.org/0000-0002-1616-4179)
- Ioannis Kourtzelis (ORCID: https://orcid.org/0000-0003-3006-8885)
- Christopher John Schofield (ORCID: https://orcid.org/0000-0002-0290-6565)
- Rubén García-Martín (ORCID: https://orcid.org/0000-0003-2049-4960)
- Sabrina Gohlke (ORCID: https://orcid.org/0000-0001-9332-5637)
- Mario Gomez-Salazar (ORCID: https://orcid.org/0000-0003-3144-7983)
- Elías F. Guðmundsson (ORCID: https://orcid.org/0000-0002-7661-4872)
- Valur Emilsson (ORCID: https://orcid.org/0000-0001-9982-0524)
- Matthias Blüher (ORCID: https://orcid.org/0000-0003-0208-2065)
- Amanda S. Coutts (ORCID: https://orcid.org/0000-0002-5005-1864)
- Tim Julius Schulz (ORCID: https://orcid.org/0000-0002-8413-3972)
- C Bénézech (ORCID: https://orcid.org/0000-0002-2613-1418)
- Triantafyllos Chavakis (ORCID: https://orcid.org/0000-0002-1869-5141)
- Iris Pruñonosa Cervera
Institutions
- University of Iceland (IS)
- Helmholtz Zentrum München (DE)
- University of Oxford (GB)
- Centro Nacional de Biotecnología (ES)
- Novartis (United States) (US)
- University Hospital Leipzig (DE)
- Deutsches Diabetes-Zentrum e.V. (DE)
- Icelandic Heart Association (IS)
- German Center for Diabetes Research (DE)
- German Institute of Human Nutrition (DE)
- Paul Langerhans Institute Dresden (DE)
- The Queen's Medical Research Institute (GB)
- Heinrich Heine University Düsseldorf (DE)
- University of York (GB)
- Nottingham Trent University (GB)
- Universidad Autónoma de Madrid (ES)
- Hull York Medical School (GB)
- Technische Universität Dresden (DE)
- University of Edinburgh (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-29
- DOI
- https://doi.org/10.1038/s41467-024-51718-7
- Citations
- 6
- Primary Topic
- Adipose Tissue and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 1.63
Funders
- Nottingham Trent University
- Wellcome Trust
- International Seafood Sustainability Foundation
- Trent University
- British Heart Foundation
- University of Oxford
- Rosetrees Trust
- Technische Universität Dresden
- Háskóli Íslands
- Hjartavernd
- Novartis Institutes for BioMedical Research
- Biotechnology and Biological Sciences Research Council
- Helmholtz Zentrum München
- Centro Nacional de Biotecnología