FOXO1 is regulated by insulin and IGF1 in pituitary gonadotropes

• FOXO1 inhibits Lhb and Fshb transcription in pituitary gonadotropes.
• How FOXO1 is regulated in gonadotropes is unknown.
• Insulin and IGF1 regulate FOXO1 via the PI3K/AKT signaling pathway.
• Insulin and IGF1 are negative regulators of gonadotrope FOXO1 nuclear activity.

The FOXO1 transcription factor is important for multiple aspects of reproductive function. We previously reported that FOXO1 functions as a repressor of gonadotropin hormone synthesis, but how FOXO1 is regulated in pituitary gonadotropes is unknown. The growth factors, insulin and insulin-like growth factor I (IGF1), function as key regulators of cell proliferation, metabolism and apoptosis in multiple cell types through the PI3K/AKT signaling pathway. In this study, we found that insulin and IGF1 signaling in gonadotropes induced FOXO1 phosphorylation through the PI3K/AKT pathway in immortalized and primary cells, resulting in FOXO1 relocation from the nucleus to the cytoplasm. Furthermore, insulin administration in vivo induced phosphorylation of FOXO1 and AKT in the pituitary. Thus, insulin and IGF1 act as negative regulators of FOXO1 activity and may serve to fine-tune gonadotropin expression.