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; David J. Hodson

doi:10.1172/jci.insight.140288

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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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
Article number	e140288
Number of pages	21
Journal	JCI Insight
Volume	6
Issue number	16
Early online date	15 Jul 2021
DOIs	https://doi.org/10.1172/jci.insight.140288
Publication status	Published - 23 Aug 2021

Keywords

Endocrinology
Metabolism

ASJC Scopus subject areas

General Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1172/jci.insight.140288Licence: CC BY

Final Published VersionFinal published version, 10.1 MBLicence: CC BY

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Nasteska, D., Cuozzo, F., Viloria, K., Johnson, E. M., Thakker, A., Bany Bakar, R., Westbrook, R. L., Barlow, J. P., Hoang, M., Joseph, J. W., Lavery, G. G., Akerman, I., Cantley, J., Hodson, L., Tennant, D. A., & Hodson, D. J. (2021). Prolyl-4-hydroxylase 3 maintains β-cell glucose metabolism during fatty acid excess in mice. JCI Insight, 6(16), Article e140288. https://doi.org/10.1172/jci.insight.140288

@article{b8e29299c71c4914bec89368a6e06741,

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

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.",

keywords = "Endocrinology, Metabolism",

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

note = "D.J.H. was supported by MRC (MR/N00275X/1 and MR/S025618/1) and Diabetes UK (17/0005681) Project Grants. D.T. was supported by Cancer Research UK Grants (C42109/A26982 and C42109/A24891). J.J. was supported by the Canadian Institute of Health Research (CIHR, PJT-159552). L.H. was supported by a British Heart Foundation Senior Fellowship (FS/15/56/31645). G.G.L. was supported by a Wellcome Trust Senior Research Fellowship (104612/Z/14/Z). This project has received funding from the European Research Council (ERC) under the European Union{\textquoteright}s Horizon 2020 research and innovation programme (Starting Grant 715884 to D.J.H.). We thank Dr Mathew Coleman (University of Birmingham) for useful discussions.",

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",

}

Nasteska, D, Cuozzo, F, Viloria, K, Johnson, EM, Thakker, A, Bany Bakar, R, Westbrook, RL, Barlow, JP, Hoang, M, Joseph, JW, Lavery, GG, Akerman, I, Cantley, J, Hodson, L, Tennant, DA & Hodson, DJ 2021, 'Prolyl-4-hydroxylase 3 maintains β-cell glucose metabolism during fatty acid excess in mice', JCI Insight, vol. 6, no. 16, e140288. https://doi.org/10.1172/jci.insight.140288

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 M.

AU - Thakker, Alpesh

AU - Bany Bakar, Rula

AU - Westbrook, Rebecca L.

AU - Barlow, Jonathan P.

AU - Hoang, Monica

AU - Joseph, Jamie W.

AU - Lavery, Gareth G.

AU - Akerman, Ildem

AU - Cantley, James

AU - Hodson, Leanne

AU - Tennant, Daniel A.

AU - Hodson, David J.

N1 - D.J.H. was supported by MRC (MR/N00275X/1 and MR/S025618/1) and Diabetes UK (17/0005681) Project Grants. D.T. was supported by Cancer Research UK Grants (C42109/A26982 and C42109/A24891). J.J. was supported by the Canadian Institute of Health Research (CIHR, PJT-159552). L.H. was supported by a British Heart Foundation Senior Fellowship (FS/15/56/31645). G.G.L. was supported by a Wellcome Trust Senior Research Fellowship (104612/Z/14/Z). This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Starting Grant 715884 to D.J.H.). We thank Dr Mathew Coleman (University of Birmingham) for useful discussions.

PY - 2021/8/23

Y1 - 2021/8/23

N2 - 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.

AB - 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.

KW - Endocrinology

KW - Metabolism

UR - http://www.scopus.com/inward/record.url?scp=85113384296&partnerID=8YFLogxK

U2 - 10.1172/jci.insight.140288

DO - 10.1172/jci.insight.140288

M3 - Article

C2 - 34264866

SN - 2379-3708

VL - 6

JO - JCI Insight

JF - JCI Insight

IS - 16

M1 - e140288

ER -

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

Abstract

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UN SDGs

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