Figure 2.

Postprandial conditions lead to FoxO nuclear exclusion via PI3K/AKT pathway activation. Under healthy conditions in the postprandial state, insulin is released from pancreatic B-cells and binds to insulin receptors in several different tissues. Activation of the receptor tyrosine-kinases leads to recruitment of insulin receptor substrate (IRS) and initiation of the PI3K/AKT signaling cascade. PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP₂), generating phosphatidylinositol-3,4,5-triphosphate (PIP₃). Subsequently, PDK1 phosphorylates and activates AKT. Phosphorylated AKT phosphorylates FoxO, which promotes recruitment of Exportin 1 and nuclear exclusion. 14-3-3 protein is also recruited and covers FoxO's NLS, inhibiting nuclear reentry. Activation of the PI3K/AKT pathway causes cytoplasmic retention and decreases the transcriptional capacity of FoxO. Created with BioRender.com.