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

Diabetologia. 2016 Jul;59(7):1503-1512. doi: 10.1007/s00125-016-3963-y. Epub 2016 Apr 30.


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.

Keywords: Food intake; Glucose homeostasis; Insulin; Insulin resistance; Knock-in leptin; Leptin resistance; Mouse gene targeting; Obesity; PI3K.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism
  • Animals
  • Blotting, Western
  • Cell Line
  • Eating / genetics
  • Eating / physiology
  • Glucose / metabolism
  • Homeostasis / genetics
  • Homeostasis / physiology
  • Hypothalamus / metabolism
  • Insulin / metabolism
  • Insulin Resistance / genetics
  • Insulin Resistance / physiology*
  • Leptin / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Obesity / genetics
  • Obesity / metabolism*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / physiology


  • Insulin
  • Leptin
  • Phosphatidylinositol 3-Kinases
  • Glucose