(A) The convergence of insulin signaling and estrogen signaling via energy sensor Sirt1 or mTOR. ERα increases the level of Sirt1, which deacetylates IRS2 (multiple lysine sites) and regulates IRS1 phosphorylation, and it regulates downstream PI3K-Akt-FoxOs signaling. ERα interacts with FoxOs through the phosphorylation of mTORC2 on Akt (Ser473) and Akt (Thr308) on FoxOs, at the same time, FoxOs transcriptionally regulate Sestrins, which regulates mTOR signaling. (B) Estrogen- ERα cascade activates PI3K-Akt-FoxO1 independent of IRS-mediated insulin signaling and suppresses gluconeogenesis. Estrogen signaling activates FoxO3, which might be due to the compensatory role of FoxO3 for FoxO1 deactivation.