Inactivation of the Class II PI3K-C2β Potentiates Insulin Signaling and Sensitivity

Samira Alliouachene, Benoit Bilanges, Gaëtan Chicanne, Karen E. Anderson, Wayne Pearce, Khaled Ali, Colin Valet, York Posor, Pei Ching Low, Claire Chaussade, Cheryl L. Scudamore, Rachel S. Salamon, Jonathan M. Backer, Len Stephens, Phill T. Hawkins, Bernard Payrastre, Bart Vanhaesebroeck

Research output: Contribution to journalArticle

35 Scopus citations

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-C2β 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-C2β inhibition selectively enhances insulin signaling only in metabolic tissues. In a primary hepatocyte model, basal PI3P lipid levels are reduced by 60% upon PI3K-C2β 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-C2β as a critical regulator of endosomal trafficking, specifically in insulin signaling, and identify PI3K-C2β as a potential drug target for insulin sensitization.

Original languageEnglish (US)
Pages (from-to)1881-1894
Number of pages14
JournalCell Reports
Volume13
Issue number9
DOIs
StatePublished - Dec 1 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Alliouachene, S., Bilanges, B., Chicanne, G., Anderson, K. E., Pearce, W., Ali, K., Valet, C., Posor, Y., Low, P. C., Chaussade, C., Scudamore, C. L., Salamon, R. S., Backer, J. M., Stephens, L., Hawkins, P. T., Payrastre, B., & Vanhaesebroeck, B. (2015). Inactivation of the Class II PI3K-C2β Potentiates Insulin Signaling and Sensitivity. Cell Reports, 13(9), 1881-1894. https://doi.org/10.1016/j.celrep.2015.10.052