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

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Abstract

© 2016, The Author(s). 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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Alliouachene, S., Bilanges, B., Chaussade, C., Pearce, W., Foukas, L. C., Scudamore, C. L., … Vanhaesebroeck, B. (2016). Inactivation of class II PI3K-C2α induces leptin resistance, age-dependent insulin resistance and obesity in male mice. Diabetologia, 59(7), 1503–1512. https://doi.org/10.1007/s00125-016-3963-y

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