PI3K-C2γ is a Rab5 effector selectively controlling endosomal Akt2 activation downstream of insulin signalling

摘要: In the liver, insulin-mediated activation of phosphatidylinositol 3-kinase (PI3K)/Akt pathway is at core metabolic control. Multiple PI3K and Akt isoenzymes are found in hepatocytes whether isoform-selective interplays exist currently unclear. Here we report that insulin signalling triggers association liver-specific class II isoform γ (PI3K-C2γ) with Rab5-GTP, its recruitment to Rab5-positive early endosomes. these vesicles, PI3K-C2γ produces a phosphatidylinositol-3,4-bisphosphate pool specifically required for delayed sustained endosomal Akt2 stimulation. Accordingly, loss does not affect insulin-dependent Akt1 as well S6K FoxO1-3 phosphorylation, but selectively reduces activation, which inhibits glycogen synthase activity. As consequence, PI3K-C2γ-deficient mice display severely reduced liver accumulation develop hyperlipidemia, adiposity resistance age or after consumption high-fat diet. Our data indicate supports an isoenzyme-specific forking signal transduction Akt2, glucose homeostasis.