| First Author | Alliouachene S | Year | 2016 |
| Journal | Diabetologia | Volume | 59 |
| Issue | 7 | Pages | 1503-1512 |
| PubMed ID | 27138914 | Mgi Jnum | J:236061 |
| Mgi Id | MGI:5804515 | Doi | 10.1007/s00125-016-3963-y |
| Citation | Alliouachene S, et al. (2016) Inactivation of class II PI3K-C2alpha induces leptin resistance, age-dependent insulin resistance and obesity in male mice. Diabetologia 59(7):1503-12 |
| abstractText | 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-C2alpha, -C2beta and -C2gamma) in metabolic regulation is just emerging. Organismal inactivation of PI3K-C2beta increases insulin signalling and sensitivity, whereas PI3K-C2gamma inactivation has a negative metabolic impact. In contrast, the role of PI3K-C2alpha in organismal metabolism remains unexplored. In this study, we investigated whether kinase inactivation of PI3K-C2alpha 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-C2alpha (Pik3c2a). RESULTS: While homozygosity for kinase-dead PI3K-C2alpha was embryonic lethal, heterozygous PI3K-C2alpha 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-C2alpha KI mice, in contrast to previous reports in which downregulation of PI3K-C2alpha in cell lines was shown to dampen insulin signalling. Interestingly, no metabolic phenotypes were detected in female PI3K-C2alpha KI mice at any age. CONCLUSIONS/INTERPRETATION: Our data uncover a sex-dependent role for PI3K-C2alpha in the modulation of hypothalamic leptin action and systemic glucose homeostasis. ACCESS TO RESEARCH MATERIALS: All reagents are available upon request. |
