Fetal PGC-1α Overexpression Programs Adult Pancreatic β-Cell Dysfunction

  1. Bertrand Blondeau1,2
  1. 1INSERM, UMRS 872, Cordeliers Research Center, Paris, France
  2. 2Université Pierre et Marie Curie, Paris, France
  3. 3Cell Therapy Unit, Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris, Paris, France
  4. 4Sanford-Burnham Medical Research Institute, Orlando, Florida
  5. 5CNRS UMR INSERM 952-CNRS 7224, Paris, France
  6. 6Department of Diabetes and Endocrinology, Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris, Paris, France
  7. 7Université Paris Diderot, Paris, France
  1. Corresponding author: Bertrand Blondeau, bertrand.blondeau{at}crc.jussieu.fr.

Abstract

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.

Footnotes

  • Received March 9, 2012.
  • Accepted October 24, 2012.

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  1. Diabetes vol. 62 no. 4 1206-1216
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