Coordinated regulation of hepatic FoxO1, PGC-1α and SREBP-1c facilitates insulin action and resistance

Type 2 diabetes is characterized by insulin resistance, hyperinsulinemia and hepatic overproduction of glucose and lipids. Insulin increases lipogenic enzyme expression by activating Akt and aPKC which activate SREBP-1c; this pathway is hyperactivated in insulin-resistant states. Insulin suppresses gluconeogenic enzyme expression by Akt-dependent phosphorylation/inactivation of FoxO1 and PGC-1 alpha; this pathway is impaired in insulin-resistant states by aPKC excess, which displaces Akt from scaffolding-protein WD40/ProF, where Akt phosphorylates/inhibits FoxO1. But how PGC-1 alpha and FoxO1 are coordinated in insulin action and resistance is uncertain. Here, in normal mice, we found, along with Akt and aPKC, insulin increased PGC-1 alpha association with WD40/ProF by an aPKC-dependent mechanism. However, in insulin-resistant high-fat-fed mice, like FoxO1, PGC-1 alpha phosphorylation was impaired by aPKC-mediated displacement of Akt from WD40/ProF, as aPKC inhibition diminished its association with WD40/ProF, and simultaneously restored Akt association with WD40/ProF and phosphorylation/inhibition of both PGC-1 alpha and FoxO1. Moreover, in high-fat-fed mice, in addition to activity, PGC-1 alpha expression was increased, not only by FoxO1 activation, but also, as found in human hepatocytes, by a mechanism requiring aPKC and SREBP-1c, which also increased expression and activity of PKC-iota. In high-fat-fed mice, inhibition of hepatic aPKC, not only restored Akt association with WD40/ProF and FoxO1/PGC-1 alpha phosphorylation, but also diminished expression of SREBP-1c, PGC-1 alpha, PKC-iota and gluconeogenic and lipogenic enzymes, and corrected glucose intolerance and hyperlipidemia. Conclusion: Insulin suppression of gluconeogenic enzyme expression is facilitated by coordinated inactivation of FoxO1 and PGC-1 alpha by WD40/ProF-associated Akt; but this coordination also increases vulnerability to aPKC hyperactivity, which is abetted by SREBP-1c-induced increases in PGC-1 alpha and PKC-I.