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

32 Citations (Scopus)

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 thatclass II PI3K-C2β kinase-dead mice are viable and healthy but display an unanticipated enhanced insulin sensitivity and glucose tolerance, as well asprotection 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. Organismal roles of class II PI3Ks are unclear. Alliouachene etal. show that inactivation of the class II PI3K-C2β in mice, by regulating insulin receptor trafficking, enhances insulin sensitivity and protects against high-fat-diet-induced liver steatosis. The results suggest that PI3K-C2β is a potential drug target for insulin sensitization.

Original languageEnglish (US)
JournalCell Reports
DOIs
StateAccepted/In press - Dec 11 2014

Fingerprint

1-Phosphatidylinositol 4-Kinase
Phosphatidylinositols
Insulin Resistance
Phosphotransferases
Insulin
Insulin Receptor
High Fat Diet
Fatty Liver
Nutrition
Liver
Fats
Tissue
Tissue Distribution
Pharmaceutical Preparations
Hepatocytes
Amplification
Lipids

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Alliouachene, S., Bilanges, B., Chicanne, G., Anderson, K. E., Pearce, W., Ali, K., ... Vanhaesebroeck, B. (Accepted/In press). Inactivation of the Class II PI3K-C2β Potentiates Insulin Signaling and Sensitivity. Cell Reports. https://doi.org/10.1016/j.celrep.2015.10.052

Inactivation of the Class II PI3K-C2β Potentiates Insulin Signaling and Sensitivity. / Alliouachene, Samira; Bilanges, Benoit; Chicanne, Gaëtan; Anderson, Karen E.; Pearce, Wayne; Ali, Khaled; Valet, Colin; Posor, York; Low, Pei Ching; Chaussade, Claire; Scudamore, Cheryl L.; Salamon, Rachel S.; Backer, Jonathan M.; Stephens, Len; Hawkins, Phill T.; Payrastre, Bernard; Vanhaesebroeck, Bart.

In: Cell Reports, 11.12.2014.

Research output: Contribution to journalArticle

Alliouachene, S, Bilanges, B, Chicanne, G, Anderson, KE, Pearce, W, Ali, K, Valet, C, Posor, Y, Low, PC, Chaussade, C, Scudamore, CL, Salamon, RS, Backer, JM, Stephens, L, Hawkins, PT, Payrastre, B & Vanhaesebroeck, B 2014, 'Inactivation of the Class II PI3K-C2β Potentiates Insulin Signaling and Sensitivity', Cell Reports. https://doi.org/10.1016/j.celrep.2015.10.052
Alliouachene, Samira ; Bilanges, Benoit ; Chicanne, Gaëtan ; Anderson, Karen E. ; Pearce, Wayne ; Ali, Khaled ; Valet, Colin ; Posor, York ; Low, Pei Ching ; Chaussade, Claire ; Scudamore, Cheryl L. ; Salamon, Rachel S. ; Backer, Jonathan M. ; Stephens, Len ; Hawkins, Phill T. ; Payrastre, Bernard ; Vanhaesebroeck, Bart. / Inactivation of the Class II PI3K-C2β Potentiates Insulin Signaling and Sensitivity. In: Cell Reports. 2014.
@article{c04844d5d9f144caa75e6077d426db12,
title = "Inactivation of the Class II PI3K-C2β 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 thatclass II PI3K-C2β kinase-dead mice are viable and healthy but display an unanticipated enhanced insulin sensitivity and glucose tolerance, as well asprotection 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. Organismal roles of class II PI3Ks are unclear. Alliouachene etal. show that inactivation of the class II PI3K-C2β in mice, by regulating insulin receptor trafficking, enhances insulin sensitivity and protects against high-fat-diet-induced liver steatosis. The results suggest that PI3K-C2β is a potential drug target for insulin sensitization.",
author = "Samira Alliouachene and Benoit Bilanges and Ga{\"e}tan Chicanne and Anderson, {Karen E.} and Wayne Pearce and Khaled Ali and Colin Valet and York Posor and Low, {Pei Ching} and Claire Chaussade and Scudamore, {Cheryl L.} and Salamon, {Rachel S.} and Backer, {Jonathan M.} and Len Stephens and Hawkins, {Phill T.} and Bernard Payrastre and Bart Vanhaesebroeck",
year = "2014",
month = "12",
day = "11",
doi = "10.1016/j.celrep.2015.10.052",
language = "English (US)",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",

}

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

PY - 2014/12/11

Y1 - 2014/12/11

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 thatclass II PI3K-C2β kinase-dead mice are viable and healthy but display an unanticipated enhanced insulin sensitivity and glucose tolerance, as well asprotection 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. Organismal roles of class II PI3Ks are unclear. Alliouachene etal. show that inactivation of the class II PI3K-C2β in mice, by regulating insulin receptor trafficking, enhances insulin sensitivity and protects against high-fat-diet-induced liver steatosis. The results suggest that PI3K-C2β is 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 thatclass II PI3K-C2β kinase-dead mice are viable and healthy but display an unanticipated enhanced insulin sensitivity and glucose tolerance, as well asprotection 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. Organismal roles of class II PI3Ks are unclear. Alliouachene etal. show that inactivation of the class II PI3K-C2β in mice, by regulating insulin receptor trafficking, enhances insulin sensitivity and protects against high-fat-diet-induced liver steatosis. The results suggest that PI3K-C2β is a potential drug target for insulin sensitization.

UR - http://www.scopus.com/inward/record.url?scp=84947604001&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84947604001&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2015.10.052

DO - 10.1016/j.celrep.2015.10.052

M3 - Article

C2 - 26655903

AN - SCOPUS:84947604001

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

ER -