Abstract
In the liver, insulin-mediated activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is at the core of metabolic control. Multiple PI3K and Akt isoenzymes are found in hepatocytes and whether isoform-selective interplays exist is currently unclear. Here we report that insulin signalling triggers the association of the liver-specific class II PI3K isoform γ (PI3K-C2γ) with Rab5-GTP, and its recruitment to Rab5-positive early endosomes. In these vesicles, PI3K-C2γ produces a phosphatidylinositol-3,4-bisphosphate pool specifically required for delayed and sustained endosomal Akt2 stimulation. Accordingly, loss of PI3K-C2γ does not affect insulin-dependent Akt1 activation as well as S6K and FoxO1-3 phosphorylation, but selectively reduces Akt2 activation, which specifically inhibits glycogen synthase activity. As a consequence, PI3K-C2γ-deficient mice display severely reduced liver accumulation of glycogen and develop hyperlipidemia, adiposity as well as insulin resistance with age or after consumption of a high-fat diet. Our data indicate PI3K-C2γ supports an isoenzyme-specific forking of insulin-mediated signal transduction to an endosomal pool of Akt2, required for glucose homeostasis.
Highlights
In the liver, insulin-mediated activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is at the core of metabolic control
The specific function of PI3K-C2g has long remained unexplored, our study provides evidence that this enzyme is critically required for delayed and sustained Akt2 activation downstream of insulin stimulation, and is necessary for the fine tuning of metabolic responses in the liver (Fig. 10)
Random fed (8 mo) by reduced glycogen synthase (GS) activation after refeeding and consequent decreased hepatic glycogen accumulation. Such a condition can be sufficient to trigger insulin resistance, as mice with heterozygous loss of protein targeting to glycogen, a scaffold protein involved in glycogen synthesis, show significant reduction in liver glycogen and an attenuated insulin receptor signalling26
Summary
Insulin-mediated activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is at the core of metabolic control. PtdIns[3,4]P2 can be produced from PtdIns[3,4,5]P3 by the action of the enzyme 5-phosphatase, Src homology 2 domain containing inositol phosphatase 2 (SHIP2), other potential sources of this lipid are the three class II PI3Ks (PI3K-C2a, b and g), which are known to produce in vitro both PtdIns[3,4]P2 and PtdIns3P In line with this view, PI3K-C2a has been found to promote endocytosis by producing a pool of PtdIns[3,4]P2 on clathrin-coated pits that is crucial to recruit Sorting nexin 9 and dynamin, two key elements supporting the maturation of pits into endocytic vesicles. In the absence of this specific signal transduction branch, the mouse liver fails to accumulate glycogen and promotes a shunt towards triglycerides production, triggering age- or diet-related insulin resistance and adiposity
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