Wang, Rongling, Gomez Salazar, Mario, Pruñonosa Cervera, Iris et al. (19 more authors) (2024) Adipocyte deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality. Nature Communications. 7483. ISSN 2041-1723
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2024. The Author(s). |
Keywords: | Animals,Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism,Humans,Energy Metabolism,Mice,Adipose Tissue, Brown/metabolism,Thermogenesis/genetics,Uncoupling Protein 1/metabolism,Male,Mice, Knockout,Female,Basic Helix-Loop-Helix Transcription Factors/metabolism,Adipocytes/metabolism,Oxygen/metabolism,Mice, Inbred C57BL,Adipocytes, Brown/metabolism,Adult,Promoter Regions, Genetic,Middle Aged |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Hull York Medical School (York) |
Depositing User: | Pure (York) |
Date Deposited: | 15 Nov 2024 10:30 |
Last Modified: | 23 Jan 2025 00:36 |
Published Version: | https://doi.org/10.1038/s41467-024-51718-7 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1038/s41467-024-51718-7 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:219693 |
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Description: Adipocyte deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality
Licence: CC-BY 2.5