Vps34 PI 3-kinase inactivation enhances insulin sensitivity through reprogramming of mitochondrial metabolism

Benoit Bilanges (), Samira Alliouachene, Wayne Pearce, Daniele Morelli, Gyorgy Szabadkai, Yuen-Li Chung, Gaëtan Chicanne, Colin Valet, Julia M. Hill, Peter J. Voshol, Lucy Collinson, Christopher Peddie, Khaled Ali, Essam Ghazaly, Vinothini Rajeeve, Georgios Trichas, Shankar Srinivas, Claire Chaussade, Rachel S. Salamon, Jonathan M. Backer, Cheryl L. Scudamore, Maria A. Whitehead, Erin P. Keaney, Leon O. Murphy, Robert K. Semple, Bernard Payrastre, Sharon A. Tooze and Bart Vanhaesebroeck ()
Additional contact information
Benoit Bilanges: University College London
Samira Alliouachene: University College London
Wayne Pearce: University College London
Daniele Morelli: University College London
Gyorgy Szabadkai: University College London
Yuen-Li Chung: The Institute of Cancer Research London
Gaëtan Chicanne: Institut des Maladies Métaboliques et Cardiovasculaires
Colin Valet: Institut des Maladies Métaboliques et Cardiovasculaires
Julia M. Hill: University College London
Peter J. Voshol: MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science
Lucy Collinson: Lincoln’s Inn Fields Laboratories
Christopher Peddie: Lincoln’s Inn Fields Laboratories
Khaled Ali: University College London
Essam Ghazaly: Queen Mary University of London
Vinothini Rajeeve: Queen Mary University of London
Georgios Trichas: University of Oxford
Shankar Srinivas: University of Oxford
Claire Chaussade: University College London
Rachel S. Salamon: Albert Einstein College of Medicine
Jonathan M. Backer: Albert Einstein College of Medicine
Cheryl L. Scudamore: Harwell Science and Innovation Campus
Maria A. Whitehead: University College London
Erin P. Keaney: Novartis Institutes for BioMedical Research
Leon O. Murphy: Novartis Institutes for BioMedical Research
Robert K. Semple: University of Cambridge, Addenbrooke’s Hospital
Bernard Payrastre: Institut des Maladies Métaboliques et Cardiovasculaires
Sharon A. Tooze: Lincoln’s Inn Fields Laboratories
Bart Vanhaesebroeck: University College London

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract Vps34 PI3K is thought to be the main producer of phosphatidylinositol-3-monophosphate, a lipid that controls intracellular vesicular trafficking. The organismal impact of systemic inhibition of Vps34 kinase activity is not completely understood. Here we show that heterozygous Vps34 kinase-dead mice are healthy and display a robustly enhanced insulin sensitivity and glucose tolerance, phenotypes mimicked by a selective Vps34 inhibitor in wild-type mice. The underlying mechanism of insulin sensitization is multifactorial and not through the canonical insulin/Akt pathway. Vps34 inhibition alters cellular energy metabolism, activating the AMPK pathway in liver and muscle. In liver, Vps34 inactivation mildly dampens autophagy, limiting substrate availability for mitochondrial respiration and reducing gluconeogenesis. In muscle, Vps34 inactivation triggers a metabolic switch from oxidative phosphorylation towards glycolysis and enhanced glucose uptake. Our study identifies Vps34 as a new drug target for insulin resistance in Type-2 diabetes, in which the unmet therapeutic need remains substantial.

Date: 2017
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DOI: 10.1038/s41467-017-01969-4

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