TY - JOUR
T1 - Inactivation of the Class II PI3K-C2β Potentiates Insulin Signaling and Sensitivity
AU - Alliouachene, Samira
AU - Bilanges, Benoit
AU - Chicanne, Gaëtan
AU - Anderson, Karen E.
AU - Pearce, Wayne
AU - Ali, Khaled
AU - Valet, Colin
AU - Posor, York
AU - Low, Pei Ching
AU - Chaussade, Claire
AU - Scudamore, Cheryl L.
AU - Salamon, Rachel S.
AU - Backer, Jonathan M.
AU - Stephens, Len
AU - Hawkins, Phill T.
AU - Payrastre, Bernard
AU - Vanhaesebroeck, Bart
N1 - Publisher Copyright:
© 2015 The Authors.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.celrep.2015.10.052
DO - 10.1016/j.celrep.2015.10.052
M3 - Article
C2 - 26655903
AN - SCOPUS:84947604001
SN - 2211-1247
VL - 13
SP - 1881
EP - 1894
JO - Cell Reports
JF - Cell Reports
IS - 9
ER -