Background: Class IA phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) is an integral mediator of insulin signaling. The p110 catalytic and p85 regulatory subunits of PI3K are the products of separate genes, and while they come together to make the active heterodimer, they have opposing roles in insulin signaling and action. Deletion of hepatic p110α results in an impaired insulin signal and severe insulin resistance, whereas deletion of hepatic p85α results in improved insulin sensitivity due to sustained levels of phosphatidylinositol (3,4,5)-trisphosphate. Here, we created mice with combined hepatic deletion of p110α and p85α (L-DKO) to study the impact on insulin signaling and whole body glucose homeostasis. Methods: Six-week old male flox control and L-DKO mice were studied over a period of 18 weeks, during which weight and glucose levels were monitored, and glucose tolerance tests, insulin tolerance test and pyruvate tolerance test were performed. Fasting insulin, insulin signaling mediators, PI3K activity and insulin receptor substrate (IRS)1-associated phosphatidylinositol kinase activity were examined at 10 weeks. Liver, muscle and white adipose tissue weight was recorded at 10 weeks and 25 weeks. Results: The L-DKO mice showed a blunted insulin signal downstream of PI3K, developed markedly impaired glucose tolerance, hyperinsulinemia and had decreased liver and adipose tissue weights. Surprisingly, however, these mice displayed normal hepatic glucose production, normal insulin tolerance, and intact IRS1-associated phosphatidylinositol kinase activity without compensatory upregulated signaling of other classes of PI3K. Conclusions: The data demonstrate an unexpectedly overall mild metabolic phenotype of the L-DKO mice, suggesting that lipid kinases other than PI3Ks might partially compensate for the loss of p110α/p85α by signaling through other nodes than Akt/Protein Kinase B.
Pubmed ID: 29983910 RIS Download
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
A commercial antibody supplier and provider of various services.
View all literature mentionsCommercial vendor and service provider of laboratory reagents and antibodies. Supplier of scientific instrumentation, reagents and consumables, and software services.
View all literature mentionsPrivately held company that develops and produces antibodies, ELISA kits, ChIP kits, proteomic kits, and other related reagents used to study cell signaling pathways that impact human health.
View all literature mentionsA commercial antibody supplier which supplies primary and secondary antibodies, biochemicals, proteins, peptides, lysates, immunoassays and other kits.
View all literature mentionsThis monoclonal secondary targets IgG
View all literature mentionsThis unknown targets IgG
View all literature mentionsThis monoclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsThis monoclonal targets Phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204)
View all literature mentionsThis monoclonal targets PI3 Kinase p85
View all literature mentionsThis monoclonal targets PIK3R1
View all literature mentionsThis polyclonal targets Phospho-p70 S6 Kinase (Thr389)
View all literature mentionsThis monoclonal targets Phospho-Akt (Thr308) (C31E5E) Rabbit mAb
View all literature mentionsThis polyclonal targets Phospho-Akt (Ser473)
View all literature mentionsThis monoclonal targets PI3 Kinase Class III
View all literature mentionsThis monoclonal targets PI3 Kinase p101 (D32A5) Rabbit mAb
View all literature mentionsThis monoclonal targets PIK3CA
View all literature mentionsThis polyclonal targets IRS-1 (C-20)
View all literature mentionsThis monoclonal targets Irs1
View all literature mentionsThis monoclonal secondary targets IgG
View all literature mentionsThis unknown targets IgG
View all literature mentionsThis monoclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsThis monoclonal targets Phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204)
View all literature mentionsThis monoclonal targets PI3 Kinase p85
View all literature mentionsThis monoclonal targets PIK3R1
View all literature mentionsThis polyclonal targets Phospho-p70 S6 Kinase (Thr389)
View all literature mentionsThis monoclonal targets Phospho-Akt (Thr308) (C31E5E) Rabbit mAb
View all literature mentionsThis polyclonal targets Phospho-Akt (Ser473)
View all literature mentionsThis monoclonal targets PI3 Kinase Class III
View all literature mentionsThis monoclonal targets PI3 Kinase p101 (D32A5) Rabbit mAb
View all literature mentionsThis monoclonal targets PIK3CA
View all literature mentionsThis polyclonal targets IRS-1 (C-20)
View all literature mentionsThis monoclonal targets Irs1
View all literature mentions