The online version of this article (doi:10.1007/s00125-016-3963-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Samira Alliouachene, Benoit Bilanges and Claire Chaussade contributed equally to this work.
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.
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).
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.
Our data uncover a sex-dependent role for PI3K-C2α in the modulation of hypothalamic leptin action and systemic glucose homeostasis.
All reagents are available upon request.
Kitatani K, Usui T, Sriraman SK et al (2015) Ceramide limits phosphatidylinositol-3-kinase C2beta-controlled cell motility in ovarian cancer: potential of ceramide as a metastasis-suppressor lipid. Oncogene. doi: 10.1038/onc.2015.330
Franco I, Margaria JP, De Santis MC et al (2015) Phosphoinositide 3-kinase-C2alpha regulates polycystin-2 ciliary entry and protects against kidney cyst formation. J Am Soc Nephrol JASN. doi: 10.1681/ASN.2012111089
Chua SC Jr, Chung WK, Wu-Peng XS et al (1996) Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science (New York, NY) 271:994–996 CrossRef
Okkenhaug K, Bilancio A, Farjot G et al (2002) Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science (New York, NY) 297:1031–1034
- Inactivation of class II PI3K-C2α induces leptin resistance, age-dependent insulin resistance and obesity in male mice
Lazaros C. Foukas
Cheryl L. Scudamore
Larissa S. Moniz
- Springer Berlin Heidelberg
Neu im Fachgebiet Innere Medizin
Meistgelesene Bücher aus der Inneren Medizin
e.Med Kampagnen-Visual, Mail Icon II