title: Inactivation of class II PI3K-C2α induces leptin resistance, age-dependent insulin resistance and obesity in male mice.
abstract: 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.
authors.affiliation: UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6DD, UK. s.alliouachene@ucl.ac.uk.
authors.forename: Samira
authors.initials: S
authors.lastname: Alliouachene
authors.affiliation: UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6DD, UK. b.bilanges@ucl.ac.uk.
authors.forename: Benoit
authors.initials: B
authors.lastname: Bilanges
authors.affiliation: UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6DD, UK.|Galderma R&D, Sophia Antipolis Cedex, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Chaussade
authors.affiliation: UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6DD, UK.
authors.forename: Wayne
authors.initials: W
authors.lastname: Pearce
authors.affiliation: Institute of Healthy Ageing and Department of Genetics, Evolution and Environment, University College London, London, UK.
authors.forename: Lazaros C
authors.initials: LC
authors.lastname: Foukas
authors.affiliation: Mary Lyon Centre, MRC Harwell, Harwell Science and Innovation Campus, Harwell, UK.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Scudamore
authors.affiliation: UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6DD, UK.
authors.forename: Larissa S
authors.initials: LS
authors.lastname: Moniz
authors.affiliation: UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6DD, UK. bart.vanh@ucl.ac.uk.
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D004435:Eating / Q000235:genetics / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D007031:Hypothalamus / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D020738:Leptin / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D007328:Insulin; D020738:Leptin; D019869:Phosphatidylinositol 3-Kinases; D005947:Glucose
keywords: Food intake; Glucose homeostasis; Insulin; Insulin resistance; Knock-in leptin; Leptin resistance; Mouse gene targeting; Obesity; PI3K