FOXO1 regulation of luteinizing hormone beta transcription

Abstract

Luteinizing hormone (LH) is required for mammalian fertility and is produced exclusively by gonadotrope cells within the anterior pituitary. Insulin stimulation of gonadotropes induces LH production, although the mechanisms are unknown. One candidate that may transduce insulin signaling into functional changes in Lhb synthesis is the Forkhead box‐O (FOXO) family of transcription factors. In response to insulin, FOXOs are negatively regulated by Akt phosphorylation, which results in their export from the nucleus to the cytoplasm, thereby limiting their nuclear activity. We have identified FOXO1 expression in murine pituitary gonadotropes and in LbT2 cells, an immortalized gonadotrope cell line. Here, we investigate insulin regulation FOXO1 and the ability of FOXO1 to alter Lhb synthesis. Western analyses identified phosphorylation changes in FOXO1 in response to insulin, which correlated with FOXO1 cytoplasmic localization using immunofluorescence imaging. By luciferase assay, we determined that FOXO1 overexpression in LbT2 cells inhibits basal and gonadotropin‐releasing hormone induced Lhb transcription. Our results indicate that FOXO1 is regulated by insulin in gonadotropes and FOXO1 inhibits Lhb synthesis. In summary, our findings identify a novel mechanism for Lhb gene regulation.Support: T31 HD720329, R01 HD067448, K01 DK080467, P30 DK063491, and U54 HD012303.