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

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Prolyl-4-hydroxylase 3 maintains β-cell glucose metabolism during fatty acid excess in mice. / Nasteska, Daniela; Cuozzo, Federica; Viloria, Katrina; Johnson, Elspeth; Thakker, Alpesh; Bakar, Rula Bany; Westbrook, Rebecca; Barlow, Johnathan; Hoang, Monica ; Joseph, Jamie ; Lavery, Gareth; Akerman, Ildem; Cantley, James; Hodson, Leanne; Tennant, Daniel; Hodson, David.

In: JCI Insight, Vol. 6, No. 16, e140288, 23.08.2021.

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Nasteska, Daniela ; Cuozzo, Federica ; Viloria, Katrina ; Johnson, Elspeth ; Thakker, Alpesh ; Bakar, Rula Bany ; Westbrook, Rebecca ; Barlow, Johnathan ; Hoang, Monica ; Joseph, Jamie ; Lavery, Gareth ; Akerman, Ildem ; Cantley, James ; Hodson, Leanne ; Tennant, Daniel ; Hodson, David. / Prolyl-4-hydroxylase 3 maintains β-cell glucose metabolism during fatty acid excess in mice. In: JCI Insight. 2021 ; Vol. 6, No. 16.

Bibtex

@article{307ee4dda6bc4bed811d621c543e5a78,
title = "Prolyl-4-hydroxylase 3 maintains β-cell glucose metabolism during fatty acid excess in mice",
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.",
keywords = "Beta cells, Bioenergetics, Endocrinology, Insulin, Metabolism",
author = "Daniela Nasteska and Federica Cuozzo and Katrina Viloria and Elspeth Johnson and Alpesh Thakker and Bakar, {Rula Bany} and Rebecca Westbrook and Johnathan Barlow and Monica Hoang and Jamie Joseph and Gareth Lavery and Ildem Akerman and James Cantley and Leanne Hodson and Daniel Tennant and David Hodson",
year = "2021",
month = aug,
day = "23",
doi = "10.1172/jci.insight.140288",
language = "English",
volume = "6",
journal = "JCI Insight",
issn = "2379-3708",
publisher = "American Society for Clinical Investigation",
number = "16",

}

RIS

TY - JOUR

T1 - Prolyl-4-hydroxylase 3 maintains β-cell glucose metabolism during fatty acid excess in mice

AU - Nasteska, Daniela

AU - Cuozzo, Federica

AU - Viloria, Katrina

AU - Johnson, Elspeth

AU - Thakker, Alpesh

AU - Bakar, Rula Bany

AU - Westbrook, Rebecca

AU - Barlow, Johnathan

AU - Hoang, Monica

AU - Joseph, Jamie

AU - Lavery, Gareth

AU - Akerman, Ildem

AU - Cantley, James

AU - Hodson, Leanne

AU - Tennant, Daniel

AU - Hodson, David

PY - 2021/8/23

Y1 - 2021/8/23

N2 - 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.

AB - 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.

KW - Beta cells

KW - Bioenergetics

KW - Endocrinology

KW - Insulin

KW - Metabolism

U2 - 10.1172/jci.insight.140288

DO - 10.1172/jci.insight.140288

M3 - Article

VL - 6

JO - JCI Insight

JF - JCI Insight

SN - 2379-3708

IS - 16

M1 - e140288

ER -