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Wang, R.* ; Gomez Salazar, M.* ; Pruñonosa Cervera, I.* ; Coutts, A.* ; French, K.* ; Pinto, M.M.* ; Gohlke, S.* ; Garcia-Martin, R.* ; Blüher, M. ; Schofield, C.J.* ; Kourtzelis, I.* ; Stimson, R.H.* ; Bénézech, C.* ; Christian, M.* ; Schulz, T.J.* ; Gudmundsson, E.F.* ; Jennings, L.L.* ; Gudnason, V.G.* ; Chavakis, T. ; Morton, N.M.* ; Emilsson, V.* ; Michailidou, Z.*

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

Nat. Commun. 15:7483 (2024)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Brown Adipose-tissue; Optimal Housing Temperatures; Thermal Environment; Kidney-disease; Hif-alpha; Hypoxia; Thermogenesis; Glucose; Obesity; Protects
Sprache englisch
Veröffentlichungsjahr 2024
HGF-Berichtsjahr 2024
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Zeitschrift Nature Communications
Quellenangaben Band: 15, Heft: 1, Seiten: , Artikelnummer: 7483 Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Begutachtungsstatus Peer reviewed
Institut(e) Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
Institute of Pancreatic Islet Research (IPI)
POF Topic(s) 30201 - Metabolic Health
90000 - German Center for Diabetes Research
Forschungsfeld(er) Helmholtz Diabetes Center
PSP-Element(e) G-506501-001
G-502600-008
Förderungen NHS Research Scotland (NRS), through the Edinburgh Clinical Research Facility
Chief Scientist Office
Rosetrees Trust
Wellcome Trust - Academy of Medical Sciences
Wellcome Trust ISSF3
British Heart Foundation/University of Edinburgh Centre of Research Excellence Award
DOI 10.1038/s41467-024-51718-7
WOS ID 001458005800001
Scopus ID 85202872948
PubMed ID 39209825
Erfassungsdatum 2024-10-09
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