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

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-C2 alpha, -C2 beta and -C2 gamma) in metabolic regulation is just emerging. Organismal inactivation of PI3K-C2 beta increases insulin signalling and sensitivity, whereas PI3K-C2 gamma inactivation has a negative metabolic impact. In contrast, the role of PI3K-C2 alpha in organismal metabolism remains unexplored. In this study, we investigated whether kinase inactivation of PI3K-C2 alpha 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-C2 alpha (Pik3c2a). Results While homozygosity for kinase-dead PI3K-C2 alpha was embryonic lethal, heterozygous PI3K-C2 alpha 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-C2 alpha KI mice, in contrast to previous reports in which downregulation of PI3K-C2 alpha in cell lines was shown to dampen insulin signalling. Interestingly, no metabolic phenotypes were detected in female PI3K-C2 alpha KI mice at any age. Conclusions/interpretation Our data uncover a sex-dependent role for PI3K-C2 alpha in the modulation of hypothalamic leptin action and systemic glucose homeostasis.