IRS1 and Insulin resistance: Moreover, there was a significant downregulation of phospho-Akt (Ser473), a key mediator in insulin signaling, which phosphorylates GSK3β at Ser9 and keeps it inactive, and IRS-1, a target of free fatty acids in insulin resistance, in retinae from mice with HFD (Fig. 4a), suggesting that abnormal hyperphosphorylation of tau in retinae may be attributed to HFD-induced dysregulation of IRS1/Akt/GSK3β signaling.