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

Nat Commun. 2024 Aug 29;15(1):7483. doi: 10.1038/s41467-024-51718-7.

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.

MeSH terms

  • Adipocytes / metabolism
  • Adipocytes, Brown / metabolism
  • Adipose Tissue, Brown* / metabolism
  • Adult
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Energy Metabolism*
  • Female
  • Humans
  • Hypoxia-Inducible Factor-Proline Dioxygenases* / genetics
  • Hypoxia-Inducible Factor-Proline Dioxygenases* / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Oxygen / metabolism
  • Promoter Regions, Genetic
  • Thermogenesis* / genetics
  • Uncoupling Protein 1* / genetics
  • Uncoupling Protein 1* / metabolism

Substances

  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Uncoupling Protein 1
  • Egln1 protein, mouse
  • EGLN1 protein, human
  • Ucp1 protein, mouse
  • endothelial PAS domain-containing protein 1
  • Basic Helix-Loop-Helix Transcription Factors
  • Oxygen
  • UCP1 protein, human