Inactivation of the Class II PI3K-C2? Potentiates Insulin Signaling and Sensitivity.

ABSTRACT: In contrast to the class I phosphoinositide 3-kinases (PI3Ks), the organismal roles of the kinase activity of the class II PI3Ks are less clear. Here, we report that class II PI3K-C2? kinase-dead mice are viable and healthy but display an unanticipated enhanced insulin sensitivity and glucose tolerance, as well as protection against high-fat-diet-induced liver steatosis. Despite having a broad tissue distribution, systemic PI3K-C2? inhibition selectively enhances insulin signaling only in metabolic tissues. In a primary hepatocyte model, basal PI3P lipid levels are reduced by 60% upon PI3K-C2? inhibition. This results in an expansion of the very early APPL1-positive endosomal compartment and altered insulin receptor trafficking, correlating with an amplification of insulin-induced, class I PI3K-dependent Akt signaling, without impacting MAPK activity. These data reveal PI3K-C2? as a critical regulator of endosomal trafficking, specifically in insulin signaling, and identify PI3K-C2? as a potential drug target for insulin sensitization.

SUBMITTER: Alliouachene S 

PROVIDER: S-EPMC4675724 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature