Fig. 4

Proposed mechanisms of 20-hydroxyecdysone action in the liver. 20E increases hepatic function by decreasing hepatic gluconeogenesis via both insulin-dependent downstream PI3K/Akt activation and insulin-independent pathways. 20E activates pAkt Ser⁴⁷³, which is the IRS substrate in the insulin signaling pathway. The activation of Akt caused the inhibition of FOXO1 to translocate into the nucleus through pFOXO1 Ser²⁵⁶. FOXO1 is an important protein that activates PEPCK and G6Pase gene expression. The inhibition of FOXO1 causes a reduction in hepatic gluconeogenesis. 20E also activates AMPKα via pAMPKα Thr¹⁷², which causes the suppression of CREB action that normally helps stabilize FOXO1 action inside the nucleus. 20E increases FGF21 expression, which then leads to the activation of pAMPKα Thr¹⁷²