Foxo1 Corepressor (FCoR) and Foxo1 Regulate a-Cell and ß-Cell Identity

We previously identified a Foxo1 binding protein; Foxo1 CoRepressor (FCoR), in adipocytes. FCoR inhibits Foxo1 activity by enhancing its acetylation. FCoR is expressed in pancreatic α- and β-cells from the embryonic stage. Fcor knockout mice (FcorKO) show impaired glucose tolerance, decreased insulin secretion, increased glucagon secretion and increased α-cell mass. We have shown that FCoR suppresses the expression of master α-cell regulatory transcription factor Aristaless-related homeobox (Arx) by increasing the methylation of the CpG-rich promoter region, while Foxo1 induces Arx expression by hypomethylation of this area. These results suggest that FCoR and Foxo1 have an opposing action in the regulation of Arx expression and α-cell mass. We studied how Foxo1 regulates Arx expression. Arx promoter region contains a conserved forkhead responsive element (FRE). Foxo1 binds to the FRE and induces Arx expression. Binding of Foxo1 to the Arx promoter dissociates binding of DNA methyltransferase 3a (Dnmt3a), and this may result in hypomethylation of the CpG rich region. Our results suggest that Arx is the target gene of Foxo1. Immunohistochemical staining of FcorKO islets showed Foxo1 nuclear localization and decreased Foxo1 in the cytosol. In isolated islets from FcorKO, we observed significant deacetylation of Foxo1, and decreased endogenous Foxo1 protein compared to control. These results are consistent with the previous finding that deacetylated Foxo1 is the active form, and is quickly ubiquitinated and degraded. To study the relationship between FCoR and Foxo1, we generated β-cell-specific Foxo1 knockout mice in the background of FcorKO (DKO). DKO showed further aggravation of glucose tolerance and insulin secretion compared to FcorKO. Foxo1 single knockout has normal glucose metabolism, thus, our results suggest that Foxo1 is activated to maintain β-cell function in FcorKO. We provide evidence that FCoR and Foxo1 function in harmonization to regulate pancreatic α-cell and β-cell identity.