Fetal PGC-1a Overexpression Programs Adult Pancreatic b-Cell Dysfunction

Adult b-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 b-cell development. Here we have investigated the molecular mechanisms underlying this regulation. We showed that GCs stimulate the expression of peroxisome proliferator–activated receptor-g coactivator-1a (PGC-1a), a coregulator of the GCs receptor (GR), and that the overexpression of PGC-1a represses genes important for b-cell development and function. More precisely, PGC-1a inhibited the expression of the key b-cell transcription factor pancreatic duodenal homeobox 1 (Pdx1). This repression required the GR and was mediated through binding of a GR/PGC-1a complex to the Pdx1 promoter. To explore PGC-1a function, we generated mice with inducible b-cell PGC-1a overexpression. Mice overexpressing PGC-1a exhibited at adult age impaired glucose tolerance associated with reduced insulin secretion, decreased b-cell mass, and b-cell hypotrophy. Interestingly, PGC-1a expression in fetal life only was sufficient to impair adult b-cell function whereas b-cell PGC-1a overexpression from adult age had no consequence on b-cell function. Altogether, our results demonstrate that the GR and PGC-1a participate in the fetal programming of adult b-cell function through inhibition of Pdx1 expression. Diabetes 62:1206– 1216, 2013