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Long-term p110α PI3K inactivation exerts a beneficial effect on metabolism.

Abstract
The insulin/insulin-like growth factor-1 signalling (IIS) pathway regulates cellular and organismal metabolism and controls the rate of aging. Gain-of-function mutations in p110α, the principal mammalian IIS-responsive isoform of PI 3-kinase (PI3K), promote cancer. In contrast, loss-of-function mutations in p110α impair insulin signalling and cause insulin resistance, inducing a pre-diabetic state. It remains unknown if long-term p110α inactivation induces further metabolic deterioration over time, leading to overt unsustainable pathology. Surprisingly, we find that chronic p110α partial inactivation in mice protects from age-related reduction in insulin sensitivity, glucose tolerance and fat accumulation, and extends the lifespan of male mice. This beneficial effect of p110α inactivation derives in part from a suppressed down-regulation of insulin receptor substrate (IRS) protein levels induced by age-related hyperinsulinemia, and correlates with enhanced insulin-induced Akt signalling in aged p110α-deficient mice. This temporal metabolic plasticity upon p110α inactivation indicates that prolonged PI3K inhibition, as intended in human cancer treatment, might not negatively impact on organismal metabolism.
AuthorsLazaros C Foukas, Benoit Bilanges, Lucia Bettedi, Wayne Pearce, Khaled Ali, Sara Sancho, Dominic J Withers, Bart Vanhaesebroeck
JournalEMBO molecular medicine (EMBO Mol Med) Vol. 5 Issue 4 Pg. 563-71 (Apr 2013) ISSN: 1757-4684 [Electronic] England
PMID23483710 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.
Chemical References
  • Fats
  • Insulin
  • Insulin Receptor Substrate Proteins
  • 1-phosphatidylinositol 3-kinase p110 subunit, mouse
  • Class I Phosphatidylinositol 3-Kinases
  • Glucose
Topics
  • Animals
  • Class I Phosphatidylinositol 3-Kinases (genetics, metabolism)
  • Fats (metabolism)
  • Female
  • Gene Silencing
  • Glucose (metabolism)
  • Humans
  • Insulin (metabolism)
  • Insulin Receptor Substrate Proteins (genetics, metabolism)
  • Male
  • Metabolic Diseases (enzymology, genetics, metabolism)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Time Factors

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