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14-3-3ζ Constrains insulin secretion by regulating mitochondrial function in pancreatic β cells

While critical for neurotransmitter synthesis, 14-3-3 proteins are often assumed to have redundant functions due to their ubiquitous expression, but despite this assumption, various 14-3-3 isoforms have been implicated in regulating metabolism. We previously reported contributions of 14-3-3ζ in β ce...

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Autores principales: Mugabo, Yves, Zhao, Cheng, Tan, Ju Jing, Ghosh, Anindya, Campbell, Scott A., Fadzeyeva, Evgenia, Paré, Frédéric, Pan, Siew Siew, Galipeau, Maria, Ast, Julia, Broichhagen, Johannes, Hodson, David J., Mulvihill, Erin E., Petropoulos, Sophie, Lim, Gareth E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9089799/
https://www.ncbi.nlm.nih.gov/pubmed/35298439
http://dx.doi.org/10.1172/jci.insight.156378
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author Mugabo, Yves
Zhao, Cheng
Tan, Ju Jing
Ghosh, Anindya
Campbell, Scott A.
Fadzeyeva, Evgenia
Paré, Frédéric
Pan, Siew Siew
Galipeau, Maria
Ast, Julia
Broichhagen, Johannes
Hodson, David J.
Mulvihill, Erin E.
Petropoulos, Sophie
Lim, Gareth E.
author_facet Mugabo, Yves
Zhao, Cheng
Tan, Ju Jing
Ghosh, Anindya
Campbell, Scott A.
Fadzeyeva, Evgenia
Paré, Frédéric
Pan, Siew Siew
Galipeau, Maria
Ast, Julia
Broichhagen, Johannes
Hodson, David J.
Mulvihill, Erin E.
Petropoulos, Sophie
Lim, Gareth E.
author_sort Mugabo, Yves
collection PubMed
description While critical for neurotransmitter synthesis, 14-3-3 proteins are often assumed to have redundant functions due to their ubiquitous expression, but despite this assumption, various 14-3-3 isoforms have been implicated in regulating metabolism. We previously reported contributions of 14-3-3ζ in β cell function, but these studies were performed in tumor-derived MIN6 cells and systemic KO mice. To further characterize the regulatory roles of 14-3-3ζ in β cell function, we generated β cell–specific 14-3-3ζ–KO mice. Although no effects on β cell mass were detected, potentiated glucose-stimulated insulin secretion (GSIS), mitochondrial function, and ATP synthesis were observed. Deletion of 14-3-3ζ also altered the β cell transcriptome, as genes associated with mitochondrial respiration and oxidative phosphorylation were upregulated. Acute 14-3-3 protein inhibition in mouse and human islets recapitulated the enhancements in GSIS and mitochondrial function, suggesting that 14-3-3ζ is the critical isoform in β cells. In dysfunctional db/db islets and human islets from type 2 diabetic donors, expression of Ywhaz/YWHAZ, the gene encoding 14-3-3ζ, was inversely associated with insulin secretion, and pan–14-3-3 protein inhibition led to enhanced GSIS and mitochondrial function. Taken together, this study demonstrates important regulatory functions of 14-3-3ζ in the regulation of β cell function and provides a deeper understanding of how insulin secretion is controlled in β cells.
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spelling pubmed-90897992022-05-13 14-3-3ζ Constrains insulin secretion by regulating mitochondrial function in pancreatic β cells Mugabo, Yves Zhao, Cheng Tan, Ju Jing Ghosh, Anindya Campbell, Scott A. Fadzeyeva, Evgenia Paré, Frédéric Pan, Siew Siew Galipeau, Maria Ast, Julia Broichhagen, Johannes Hodson, David J. Mulvihill, Erin E. Petropoulos, Sophie Lim, Gareth E. JCI Insight Research Article While critical for neurotransmitter synthesis, 14-3-3 proteins are often assumed to have redundant functions due to their ubiquitous expression, but despite this assumption, various 14-3-3 isoforms have been implicated in regulating metabolism. We previously reported contributions of 14-3-3ζ in β cell function, but these studies were performed in tumor-derived MIN6 cells and systemic KO mice. To further characterize the regulatory roles of 14-3-3ζ in β cell function, we generated β cell–specific 14-3-3ζ–KO mice. Although no effects on β cell mass were detected, potentiated glucose-stimulated insulin secretion (GSIS), mitochondrial function, and ATP synthesis were observed. Deletion of 14-3-3ζ also altered the β cell transcriptome, as genes associated with mitochondrial respiration and oxidative phosphorylation were upregulated. Acute 14-3-3 protein inhibition in mouse and human islets recapitulated the enhancements in GSIS and mitochondrial function, suggesting that 14-3-3ζ is the critical isoform in β cells. In dysfunctional db/db islets and human islets from type 2 diabetic donors, expression of Ywhaz/YWHAZ, the gene encoding 14-3-3ζ, was inversely associated with insulin secretion, and pan–14-3-3 protein inhibition led to enhanced GSIS and mitochondrial function. Taken together, this study demonstrates important regulatory functions of 14-3-3ζ in the regulation of β cell function and provides a deeper understanding of how insulin secretion is controlled in β cells. American Society for Clinical Investigation 2022-04-22 /pmc/articles/PMC9089799/ /pubmed/35298439 http://dx.doi.org/10.1172/jci.insight.156378 Text en © 2022 Mugabo et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Mugabo, Yves
Zhao, Cheng
Tan, Ju Jing
Ghosh, Anindya
Campbell, Scott A.
Fadzeyeva, Evgenia
Paré, Frédéric
Pan, Siew Siew
Galipeau, Maria
Ast, Julia
Broichhagen, Johannes
Hodson, David J.
Mulvihill, Erin E.
Petropoulos, Sophie
Lim, Gareth E.
14-3-3ζ Constrains insulin secretion by regulating mitochondrial function in pancreatic β cells
title 14-3-3ζ Constrains insulin secretion by regulating mitochondrial function in pancreatic β cells
title_full 14-3-3ζ Constrains insulin secretion by regulating mitochondrial function in pancreatic β cells
title_fullStr 14-3-3ζ Constrains insulin secretion by regulating mitochondrial function in pancreatic β cells
title_full_unstemmed 14-3-3ζ Constrains insulin secretion by regulating mitochondrial function in pancreatic β cells
title_short 14-3-3ζ Constrains insulin secretion by regulating mitochondrial function in pancreatic β cells
title_sort 14-3-3ζ constrains insulin secretion by regulating mitochondrial function in pancreatic β cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9089799/
https://www.ncbi.nlm.nih.gov/pubmed/35298439
http://dx.doi.org/10.1172/jci.insight.156378
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