Enhanced β-adrenergic signalling underlies an age-dependent beneficial metabolic effect of PI3K p110α inactivation in adipose tissue

Abstract

The insulin/IGF-1 signalling pathway is a key regulator of metabolism and the rate of ageing. We previously documented that systemic inactivation of phosphoinositide 3-kinase (PI3K) p110α, the principal PI3K isoform that positively regulates insulin signalling, results in a beneficial metabolic effect in aged mice. Here we demonstrate that deletion of p110α specifically in the adipose tissue leads to less fat accumulation over a significant part of adult life and allows the maintenance of normal glucose tolerance despite insulin resistance. This effect of p110α inactivation is due to a potentiating effect on β-adrenergic signalling, which leads to increased catecholamine-induced energy expenditure in the adipose tissue. Our findings provide a paradigm of how partial inactivation of an essential component of the insulin signalling pathway can have an overall beneficial metabolic effect and suggest that PI3K inhibition could potentiate the effect of β-adrenergic agonists in the treatment of obesity and its associated comorbidities.

Increased mitochondrial and lipid metabolism is a conserved effect of Insulin/PI3K pathway downregulation in adipose tissue

“…In line with what is reported here in mouse 3T3-L1 adipocytes, parallel studies in our lab have revealed that genetic or pharmacological inactivation of p110α in the adipose tissue of mice results in enhanced adrenergic signalling, which promotes lipolysis and energy expenditure 19 . The enhancement in adrenergic signalling mitigates the effect of insulin resistance ensuing from p110α inactivation thus producing overall a lean phenotype and improved glucose homeostasis.…”

“…Consistent with upregulated mitochondrial function as result of p110α inhibition reported here, a recent study from our lab has demonstrated reduced age-dependent fat accumulation in mice with adipose tissue-specific p110α deletion using the adiponectin-Cre strain 19 . However, a previous study which used an aP2-Cre strain to delete p110α in the adipose tissue of mice has reported obesity and decreased energy expenditure 37 , which are diametrically different phenotypes from those reported in our study.…”

“…Partial inactivation of p110α by ubiquitous heterozygous mutation has been shown to confer improved metabolic profile in aged mice and to modestly extend lifespan 18 . Furthermore, adipose tissue-specific inactivation of p110α resulted in leaner mice due to increased energy expenditure 19 . Importantly, long-term pharmacological inhibition of p110α has previously been shown to protect mice and rhesus monkeys from diet-induced obesity, highlighting both the utility of PI3K inhibitors in metabolic studies and their therapeutic potential 20,21 .…”

Vav2 catalysis-dependent pathways contribute to skeletal muscle growth and metabolic homeostasis

“…However, it is worth noting that previous studies have shown that this biological readout is not a good indicator of the actual insulin sensitivity of this tissue 64,65 . In fact, similar defects in the suppression of hepatic glucose production were found in loss-of-function mouse models for signaling elements of the insulin and IGF1 pathways in both skeletal muscle (IGF1, Akt family) and WAT (PI3Kα) 16,66,67 . Our analyses also indicated that Vav2 L332A/L332A animals exhibit lower rates of insulin-induced glucose clearance than controls ( Supplementary Fig.…”

Truncation of Pik3r1 causes severe insulin resistance uncoupled from obesity and dyslipidaemia by increased energy expenditure

“…Reduced adipose mass can reflect altered energy balance rather than lipodystrophy. Reduction of PI3K pathway activity by overexpression of the lipid phosphatase Pten in mice was previously reported to enhance energy expenditure via brown adipose tissue activation [ 41 ], albeit without IR, while pharmacological or genetic inhibition of the p110α catalytic subunit of PI3K has also been associated with increased energy expenditure [ [40] , [41] , [42] , [43] ]. Moreover, a similar energetic phenotype on brown adipose-specific knockout of Pik3r1 has recently been described [ 44 ].…”