Prolyl-4-hydroxylase 3 maintains β-cell glucose metabolism during fatty acid excess in mice

Research output: Contribution to journalArticlepeer-review

Authors

  • Federica Cuozzo
  • Elspeth Johnson
  • Rula Bany Bakar
  • Rebecca Westbrook
  • Johnathan Barlow
  • Monica Hoang
  • Jamie Joseph
  • James Cantley
  • Leanne Hodson
  • Daniel Tennant
  • David Hodson

Colleges, School and Institutes

Abstract

The alpha ketoglutarate-dependent dioxygenase, prolyl-4-hydroxylase 3 (PHD3), is a Hypoxia-Inducible Factor (HIF) target that uses molecular oxygen to hydroxylate peptidyl prolyl residues. While PHD3 has been reported to influence cancer cell metabolism and liver insulin sensitivity, relatively little is known about effects of this highly conserved enzyme in insulin-secreting β-cells in vivo. Here, we show that deletion of PHD3 specifically in β-cells (βPHD3KO) is associated with impaired glucose homeostasis in mice fed high fat diet. In the early stages of dietary fat excess, βPHD3KO islets energetically rewire, leading to defects in the management of pyruvate fate and a shift from glycolysis to increased fatty acid oxidation (FAO). However, under more prolonged metabolic stress, this switch to preferential FAO in βPHD3KO islets is associated with impaired glucose-stimulated ATP/ADP rises, Ca2+ fluxes and insulin secretion. Thus, PHD3 might be a pivotal component of the β-cell glucose metabolism machinery in mice by suppressing the use of fatty acids as a primary fuel source during the early phases of metabolic stress.

Details

Original languageEnglish
Article numbere140288
Number of pages21
JournalJCI Insight
Volume6
Issue number16
Publication statusPublished - 23 Aug 2021

Keywords

  • Beta cells, Bioenergetics, Endocrinology, Insulin, Metabolism