title: 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.
authors.affiliation: Institute of Healthy Ageing and Department of Genetics, Evolution and Environment, University College London, Darwin Building, Gower Street, London, UK. l.foukas@ucl.ac.uk
authors.forename: Lazaros C
authors.initials: LC
authors.lastname: Foukas
authors.forename: Benoit
authors.initials: B
authors.lastname: Bilanges
authors.forename: Lucia
authors.initials: L
authors.lastname: Bettedi
authors.forename: Wayne
authors.initials: W
authors.lastname: Pearce
authors.forename: Khaled
authors.initials: K
authors.lastname: Ali
authors.forename: Sara
authors.initials: S
authors.lastname: Sancho
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Withers
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
mesh_terms: D000818:Animals; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism*; D005223:Fats / Q000378:metabolism; D005260:Female; D020868:Gene Silencing; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008659:Metabolic Diseases / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013997:Time Factors
chemical_list: D005223:Fats; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases; D005947:Glucose