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

摘要

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 p-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-lα (PGC-lα), a cor-egulator of the GCs receptor (GR), and that the overexpression of PGC-lα represses genes important for β-cell development and function. More precisely, PGC-lα inhibited the expression of the key β-cell transcription factor pancreatic duodenal homeo-box 1 (Pdxl). This repression required the GR and was mediated through binding of a GR/PGC-lα complex to the Pdxl promoter. To explore PGC-lα function, we generated mice with inducible P-cell PGC-lα overexpression. Mice overexpressing PGC-lα exhibited at adult age impaired glucose tolerance associated with reduced insulin secretion, decreased β-cell mass, and β-cell hypo-trophy. Interestingly, PGC-lα expression in fetal life only was sufficient to impair adult p-cell function whereas β-cell PGC-lα overexpression from adult age had no consequence on β-cell function. Altogether, our results demonstrate that the GR and PGC-la participate in the fetal programming of adult β-cell function through inhibition of Pdxl expression.