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

Rongling Wang, Mario Gomez Salazar, Iris Pruñonosa Cervera, Amanda Coutts, Karen French, Marlene Magalhaes Pinto, Sabrina Gohlke, Ruben García-Martín, Matthias Blüher, Christopher J. Schofield, Ioannis Kourtzelis, Roland H. Stimson, Cécile Bénézech, Mark Christian, Tim J. Schulz, Elias F. Gudmundsson, Lori L. Jennings, Vilmundur G. Gudnason, Triantafyllos Chavakis, Nicholas M. Morton, Valur Emilsson and Zoi Michailidou ()
Additional contact information
Rongling Wang: University of Edinburgh
Mario Gomez Salazar: University of Edinburgh
Iris Pruñonosa Cervera: University of Edinburgh
Amanda Coutts: Clifton
Karen French: University of Edinburgh
Marlene Magalhaes Pinto: University of Edinburgh
Sabrina Gohlke: Potsdam-Rehbrücke
Ruben García-Martín: Campus-UAM
Matthias Blüher: Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig
Christopher J. Schofield: Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research University of Oxford
Ioannis Kourtzelis: University of York
Roland H. Stimson: University of Edinburgh
Cécile Bénézech: University of Edinburgh
Mark Christian: Clifton
Tim J. Schulz: Potsdam-Rehbrücke
Elias F. Gudmundsson: Icelandic Heart Association
Lori L. Jennings: Novartis Institutes for Biomedical Research
Vilmundur G. Gudnason: Icelandic Heart Association
Triantafyllos Chavakis: University of Edinburgh
Nicholas M. Morton: University of Edinburgh
Valur Emilsson: Icelandic Heart Association
Zoi Michailidou: University of Edinburgh

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51718-7

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