| First Author | Valtat B | Year | 2013 |
| Journal | Diabetes | Volume | 62 |
| Issue | 4 | Pages | 1206-16 |
| PubMed ID | 23274887 | Mgi Jnum | J:208586 |
| Mgi Id | MGI:5563736 | Doi | 10.2337/db12-0314 |
| Citation | Valtat B, et al. (2013) Fetal PGC-1alpha overexpression programs adult pancreatic beta-cell dysfunction. Diabetes 62(4):1206-16 |
| abstractText | Adult beta-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 beta-cell development. Here we have investigated the molecular mechanisms underlying this regulation. We showed that GCs stimulate the expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), a coregulator of the GCs receptor (GR), and that the overexpression of PGC-1alpha represses genes important for beta-cell development and function. More precisely, PGC-1alpha inhibited the expression of the key beta-cell transcription factor pancreatic duodenal homeobox 1 (Pdx1). This repression required the GR and was mediated through binding of a GR/PGC-1alpha complex to the Pdx1 promoter. To explore PGC-1alpha function, we generated mice with inducible beta-cell PGC-1alpha overexpression. Mice overexpressing PGC-1alpha exhibited at adult age impaired glucose tolerance associated with reduced insulin secretion, decreased beta-cell mass, and beta-cell hypotrophy. Interestingly, PGC-1alpha expression in fetal life only was sufficient to impair adult beta-cell function whereas beta-cell PGC-1alpha overexpression from adult age had no consequence on beta-cell function. Altogether, our results demonstrate that the GR and PGC-1alpha participate in the fetal programming of adult beta-cell function through inhibition of Pdx1 expression. |
