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.

The PI3K/mTOR inhibitor PF-04691502 induces apoptosis and inhibits microenvironmental signaling in CLL and the Eµ-TCL1 mouse model

“…46 Interestingly, long-term PI3Ka inhibition was not detrimental to mice and, in fact, protected against a reduction in insulin sensitivity, glucose tolerance, and fat accumulation. 47 During our study, we combined inhibitors that targeted specific isoforms of PI3K and mTOR, replicating our findings with PF-04691502. Although combining the PI3Ka/b/d/g inhibitors or idelalisib with the mTOR inhibitor everolimus induced substantial apoptosis, PF-04691502 alone still induced significantly more.…”

Role of Phosphoinositide 3-OH Kinase p110β in Skeletal Myogenesis

“…One obvious explanation for these discrepancies involves aging itself, as aging has long been known to modify glucose tolerance (53). Additionally, improved glucose tolerance in older mice possessing heterozygous knock-in of kinase-dead p110␣ (D933A) compared to that in younger mice has been reported (23,54). Together, these data and ours demonstrate that perturbations in class I PI3K catalytic subunit abundance or function differentially affect glucose tolerance in an age-dependent manner.…”

PI3Kα inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction

“…Mice carrying mutations with reduced activity of PI3Kα display decreased body weight and body length (1). Over the long term, these physiological adaptations are translated into beneficial effects on metabolic regulation and aging (11)(12)(13). However, enhanced PI3K signaling only in cells that express leptin receptor (LR) due to cell-type-specific deletion of phosphatase and tensin homolog (PTEN; LR ΔPTEN mice) generates mice with a metabolic phenotype similar to those with reduced global PI3K activity, i.e., decreased adiposity and increased energy expenditure (14).…”