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

Daniela Nasteska, Federica Cuozzo, Katrina Viloria, Elspeth Johnson, Alpesh Thakker, Rula Bany Bakar, Rebecca Westbrook, Johnathan Barlow, Monica Hoang, Jamie Joseph, Gareth Lavery, Ildem Akerman, James Cantley, Leanne Hodson, Daniel Tennant, David Hodson

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Abstract

The α-ketoglutarate-dependent dioxygenase, prolyl-4-hydroxylase 3 (PHD3), is an HIF target that uses molecular oxygen to hydroxylate peptidyl prolyl residues. Although PHD3 has been reported to influence cancer cell metabolism and liver insulin sensitivity, relatively little is known about the effects of this highly conserved enzyme in insulin-secreting β cells in vivo. Here, we show that the deletion of PHD3 specifically in β cells (βPHD3KO) was associated with impaired glucose homeostasis in mice fed a high-fat diet. In the early stages of dietary fat excess, βPHD3KO islets energetically rewired, 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 was 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.

Original languageEnglish
Article numbere140288
Number of pages21
JournalJCI Insight
Volume6
Issue number16
Early online date15 Jul 2021
DOIs
Publication statusPublished - 23 Aug 2021

Bibliographical note

Funding Information:
DJH was supported by MRC (MR/N00275X/1 and MR/S025618/1) and Diabetes UK (17/0005681) Project Grants. DAT was supported by Cancer Research UK Grants (C42109/A26982 and C42109/ A24891). JWJ was supported by the Canadian Institute of Health Research (CIHR, PJT-159552). LH was supported by a British Heart Foundation Senior Fellowship (FS/15/56/31645). GGL was supported by a Wellcome Trust Senior Research Fellowship (104612/Z/14/Z). This project has received funding from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (Starting Grant 715884 to DJH). We thank Mathew Coleman (University of Birmingham) for useful discussions.

Publisher Copyright:
© 2021, Nasteska et al.

Keywords

  • Beta cells
  • Bioenergetics
  • Endocrinology
  • Insulin
  • Metabolism

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