Enhanced β-adrenergic signalling underlies an age-dependent beneficial metabolic effect of PI3K p110α inactivation in adipose tissue.
Nat Commun. 2019 Apr 4;10(1):1546. doi: 10.1038/s41467-019-09514-1.
Araiz C1, Yan A1, Bettedi L1,2, Samuelson I1,3, Virtue S3, McGavigan AK3, Dani C4, Vidal-Puig A3,5, Foukas LC6.
1. Institute of Healthy Ageing & Department of Genetics, Evolution and Environment, University College London, London, WC1E 6BT, UK.
2. National Institutes of Child Health and Human Development (NICHD), Bethesda, MD, 20814, USA.
3. University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, CB2 0QQ, UK.
4. Université Côte d’Azur, CNRS, Inserm, iBV, Faculté de Médecine, 06107, Nice Cedex 2, France.
5. Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK.
6. Institute of Healthy Ageing & Department of Genetics, Evolution and Environment, University College London, London, WC1E 6BT, UK. firstname.lastname@example.org.
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.