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

Daniela Nasteska, Federica Cuozzo, Katrina Viloria, Elspeth M. Johnson, Alpesh Thakker, Rula Bany Bakar, Rebecca L. Westbrook, Jonathan P. Barlow, Monica Hoang, Jamie W. Joseph, Gareth G. Lavery, Ildem Akerman, James Cantley, Leanne Hodson, Daniel A. Tennant (Lead / Corresponding author), David J. Hodson (Lead / Corresponding author)

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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.

Original languageEnglish
JournalJCI Insight
Publication statusE-pub ahead of print - 15 Jul 2021


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