Fetal PGC-1? overexpression programs adult pancreatic ?-cell dysfunction.

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

SUBMITTER: Valtat B 

PROVIDER: S-EPMC3609553 | biostudies-other | 2013 Apr

REPOSITORIES: biostudies-other