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Open Access 01-07-2016 | Article

Inactivation of class II PI3K-C2α induces leptin resistance, age-dependent insulin resistance and obesity in male mice

Authors: Samira Alliouachene, Benoit Bilanges, Claire Chaussade, Wayne Pearce, Lazaros C. Foukas, Cheryl L. Scudamore, Larissa S. Moniz, Bart Vanhaesebroeck

Published in: Diabetologia | Issue 7/2016

Abstract

Aims/hypothesis

While the class I phosphoinositide 3-kinases (PI3Ks) are well-documented positive regulators of metabolism, the involvement of class II PI3K isoforms (PI3K-C2α, -C2β and -C2γ) in metabolic regulation is just emerging. Organismal inactivation of PI3K-C2β increases insulin signalling and sensitivity, whereas PI3K-C2γ inactivation has a negative metabolic impact. In contrast, the role of PI3K-C2α in organismal metabolism remains unexplored. In this study, we investigated whether kinase inactivation of PI3K-C2α affects glucose metabolism in mice.

Methods

We have generated and characterised a mouse line with a constitutive inactivating knock-in (KI) mutation in the kinase domain of the gene encoding PI3K-C2α (Pik3c2a).

Results

While homozygosity for kinase-dead PI3K-C2α was embryonic lethal, heterozygous PI3K-C2α KI mice were viable and fertile, with no significant histopathological findings. However, male heterozygous mice showed early onset leptin resistance, with a defect in leptin signalling in the hypothalamus, correlating with a mild, age-dependent obesity, insulin resistance and glucose intolerance. Insulin signalling was unaffected in insulin target tissues of PI3K-C2α KI mice, in contrast to previous reports in which downregulation of PI3K-C2α in cell lines was shown to dampen insulin signalling. Interestingly, no metabolic phenotypes were detected in female PI3K-C2α KI mice at any age.

Conclusions/interpretation

Our data uncover a sex-dependent role for PI3K-C2α in the modulation of hypothalamic leptin action and systemic glucose homeostasis.

Access to research materials

All reagents are available upon request.

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Title: Inactivation of class II PI3K-C2α induces leptin resistance, age-dependent insulin resistance and obesity in male mice
Authors: Samira Alliouachene
Benoit Bilanges
Claire Chaussade
Wayne Pearce
Lazaros C. Foukas
Cheryl L. Scudamore
Larissa S. Moniz
Bart Vanhaesebroeck
Publication date: 01-07-2016
Publisher: Springer Berlin Heidelberg
Published in: Diabetologia / Issue 7/2016
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-016-3963-y

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Inactivation of class II PI3K-C2α induces leptin resistance, age-dependent insulin resistance and obesity in male mice

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Access to research materials

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Aims/hypothesis

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Results

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