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Fetal PGC-1α Overexpression Programs Adult Pancreatic β-Cell Dysfunction
Adult β-cell dysfunction, a hallmark of type 2 diabetes, can be programmed by adverse fetal environment. We have shown that fetal glucocorticoids (GCs) participate in this programming through inhibition of β-cell development. Here we have investigated the molecular mechanisms underlying this regulat...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609553/ https://www.ncbi.nlm.nih.gov/pubmed/23274887 http://dx.doi.org/10.2337/db12-0314 |
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author | Valtat, Bérengère Riveline, Jean-Pierre Zhang, Ping Singh-Estivalet, Amrit Armanet, Mathieu Venteclef, Nicolas Besseiche, Adrien Kelly, Daniel P. Tronche, François Ferré, Pascal Gautier, Jean-François Bréant, Bernadette Blondeau, Bertrand |
author_facet | Valtat, Bérengère Riveline, Jean-Pierre Zhang, Ping Singh-Estivalet, Amrit Armanet, Mathieu Venteclef, Nicolas Besseiche, Adrien Kelly, Daniel P. Tronche, François Ferré, Pascal Gautier, Jean-François Bréant, Bernadette Blondeau, Bertrand |
author_sort | Valtat, Bérengère |
collection | PubMed |
description | Adult β-cell dysfunction, a hallmark of type 2 diabetes, can be programmed by adverse fetal environment. We have shown that fetal glucocorticoids (GCs) participate in this programming through inhibition of β-cell development. Here we have investigated the molecular mechanisms underlying this regulation. We showed that GCs stimulate the expression of peroxisome proliferator–activated receptor-γ coactivator-1α (PGC-1α), a coregulator of the GCs receptor (GR), and that the overexpression of PGC-1α represses genes important for β-cell development and function. More precisely, PGC-1α inhibited the expression of the key β-cell transcription factor pancreatic duodenal homeobox 1 (Pdx1). This repression required the GR and was mediated through binding of a GR/PGC-1α complex to the Pdx1 promoter. To explore PGC-1α function, we generated mice with inducible β-cell PGC-1α overexpression. Mice overexpressing PGC-1α exhibited at adult age impaired glucose tolerance associated with reduced insulin secretion, decreased β-cell mass, and β-cell hypotrophy. Interestingly, PGC-1α expression in fetal life only was sufficient to impair adult β-cell function whereas β-cell PGC-1α overexpression from adult age had no consequence on β-cell function. Altogether, our results demonstrate that the GR and PGC-1α participate in the fetal programming of adult β-cell function through inhibition of Pdx1 expression. |
format | Online Article Text |
id | pubmed-3609553 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-36095532014-04-01 Fetal PGC-1α Overexpression Programs Adult Pancreatic β-Cell Dysfunction Valtat, Bérengère Riveline, Jean-Pierre Zhang, Ping Singh-Estivalet, Amrit Armanet, Mathieu Venteclef, Nicolas Besseiche, Adrien Kelly, Daniel P. Tronche, François Ferré, Pascal Gautier, Jean-François Bréant, Bernadette Blondeau, Bertrand Diabetes Original Research Adult β-cell dysfunction, a hallmark of type 2 diabetes, can be programmed by adverse fetal environment. We have shown that fetal glucocorticoids (GCs) participate in this programming through inhibition of β-cell development. Here we have investigated the molecular mechanisms underlying this regulation. We showed that GCs stimulate the expression of peroxisome proliferator–activated receptor-γ coactivator-1α (PGC-1α), a coregulator of the GCs receptor (GR), and that the overexpression of PGC-1α represses genes important for β-cell development and function. More precisely, PGC-1α inhibited the expression of the key β-cell transcription factor pancreatic duodenal homeobox 1 (Pdx1). This repression required the GR and was mediated through binding of a GR/PGC-1α complex to the Pdx1 promoter. To explore PGC-1α function, we generated mice with inducible β-cell PGC-1α overexpression. Mice overexpressing PGC-1α exhibited at adult age impaired glucose tolerance associated with reduced insulin secretion, decreased β-cell mass, and β-cell hypotrophy. Interestingly, PGC-1α expression in fetal life only was sufficient to impair adult β-cell function whereas β-cell PGC-1α overexpression from adult age had no consequence on β-cell function. Altogether, our results demonstrate that the GR and PGC-1α participate in the fetal programming of adult β-cell function through inhibition of Pdx1 expression. American Diabetes Association 2013-04 2013-03-14 /pmc/articles/PMC3609553/ /pubmed/23274887 http://dx.doi.org/10.2337/db12-0314 Text en © 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. |
spellingShingle | Original Research Valtat, Bérengère Riveline, Jean-Pierre Zhang, Ping Singh-Estivalet, Amrit Armanet, Mathieu Venteclef, Nicolas Besseiche, Adrien Kelly, Daniel P. Tronche, François Ferré, Pascal Gautier, Jean-François Bréant, Bernadette Blondeau, Bertrand Fetal PGC-1α Overexpression Programs Adult Pancreatic β-Cell Dysfunction |
title | Fetal PGC-1α Overexpression Programs Adult Pancreatic β-Cell Dysfunction |
title_full | Fetal PGC-1α Overexpression Programs Adult Pancreatic β-Cell Dysfunction |
title_fullStr | Fetal PGC-1α Overexpression Programs Adult Pancreatic β-Cell Dysfunction |
title_full_unstemmed | Fetal PGC-1α Overexpression Programs Adult Pancreatic β-Cell Dysfunction |
title_short | Fetal PGC-1α Overexpression Programs Adult Pancreatic β-Cell Dysfunction |
title_sort | fetal pgc-1α overexpression programs adult pancreatic β-cell dysfunction |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609553/ https://www.ncbi.nlm.nih.gov/pubmed/23274887 http://dx.doi.org/10.2337/db12-0314 |
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