Fetal PGC-1α Overexpression Programs Adult Pancreatic β-Cell Dysfunction
- Bérengère Valtat1,2,
- Jean-Pierre Riveline1,2,
- Ping Zhang1,2,
- Amrit Singh-Estivalet1,2,
- Mathieu Armanet1,2,3,
- Nicolas Venteclef1,2,
- Adrien Besseiche1,2,
- Daniel P. Kelly4,
- François Tronche2,5,
- Pascal Ferré1,2,
- Jean-François Gautier1,2,6,7,
- Bernadette Bréant1,2 and
- Bertrand Blondeau1,2⇑
- 1INSERM, UMRS 872, Cordeliers Research Center, Paris, France
- 2Université Pierre et Marie Curie, Paris, France
- 3Cell Therapy Unit, Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris, Paris, France
- 4Sanford-Burnham Medical Research Institute, Orlando, Florida
- 5CNRS UMR INSERM 952-CNRS 7224, Paris, France
- 6Department of Diabetes and Endocrinology, Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris, Paris, France
- 7Université Paris Diderot, Paris, France
- Corresponding author: Bertrand Blondeau, .
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-0314/-/DC1
- Received March 9, 2012.
- Accepted October 24, 2012.
- © 2013 by the American Diabetes Association.
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