Open AccessLong‐term p110α PI3K inactivation exerts a beneficial effect on metabolism
Author(s) -
Foukas Lazaros C.,
Bilanges Benoit,
Bettedi Lucia,
Pearce Wayne,
Ali Khaled,
Sancho Sara,
Withers Dominic J.,
Vanhaesebroeck Bart
Publication year - 2013
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201201953
Subject(s) - hyperinsulinemia , insulin , pi3k/akt/mtor pathway , biology , insulin receptor , endocrinology , insulin resistance , medicine , protein kinase b , metabolism , microbiology and biotechnology , signal transduction
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.