Projects per year
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 language | English |
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Article number | e140288 |
Number of pages | 21 |
Journal | JCI Insight |
Volume | 6 |
Issue number | 16 |
Early online date | 15 Jul 2021 |
DOIs | |
Publication status | Published - 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
Fingerprint
Dive into the research topics of 'Prolyl-4-hydroxylase 3 maintains β-cell glucose metabolism during fatty acid excess in mice'. Together they form a unique fingerprint.Projects
- 2 Finished
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Investigating the role of immature beta cells in insulin release from the intact islet
Nasteska, D. & Hodson, D.
1/08/19 → 30/11/22
Project: Research
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Regulation of NAD+ metabolism in skeletal muscle during ageing and disease
Lavery, G.
1/11/14 → 30/04/21
Project: Research