Adipocyte deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality.
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
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
29 Aug 2024
29 Aug 2024
Historique:
received:
09
04
2022
accepted:
14
08
2024
medline:
1
9
2024
pubmed:
1
9
2024
entrez:
29
8
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39209825
doi: 10.1038/s41467-024-51718-7
pii: 10.1038/s41467-024-51718-7
pmc: PMC11362468
doi:
Substances chimiques
Hypoxia-Inducible Factor-Proline Dioxygenases
EC 1.14.11.29
Uncoupling Protein 1
0
Egln1 protein, mouse
EC 1.14.11.29
EGLN1 protein, human
EC 1.14.11.2
Ucp1 protein, mouse
0
endothelial PAS domain-containing protein 1
1B37H0967P
Basic Helix-Loop-Helix Transcription Factors
0
Oxygen
S88TT14065
UCP1 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
7483Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Informations de copyright
© 2024. The Author(s).
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