Fetal PGC-1α overexpression programs adult pancreatic ß-cell dysfunction.

ABSTRACT

Adult ß-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 ß-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 ß-cell development and function. More precisely, PGC-1α inhibited the expression of the key ß-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 ß-cell PGC-1α overexpression. Mice overexpressing PGC-1α exhibited at adult age impaired glucose tolerance associated with reduced insulin secretion, decreased ß-cell mass, and ß-cell hypotrophy. Interestingly, PGC-1α expression in fetal life only was sufficient to impair adult ß-cell function whereas ß-cell PGC-1α overexpression from adult age had no consequence on ß-cell function. Altogether, our results demonstrate that the GR and PGC-1α participate in the fetal programming of adult ß-cell function through inhibition of Pdx1 expression.