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

Benoît Bilanges ,Cheryl L Scudamore,Robert K Semple,Shankar Srinivas,Gaëtan Chicanne,Samira Alliouachene,Colin Valet,Salamon Rs ,Christopher J Peddie ,Backer Jm ,Georgios Trichas,Voshol Pj ,Wayne Pearce,Chung Yl ,Murphy Lo ,Essam Ghazaly,Claire Chaussade,Bernard Payrastre,Jm Hill ,Ma Whitehead ,Keaney Ep ,Daniele Morelli,Lucy M Collinson ,György Szabadkai ,Tooze Sa ,Kulsam Ali ,Rajeeve ,Bart Vanhaesebroeck

doi:10.1038/s41467-017-01969-4

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.

Highlights

Vps[34] PI3K is thought to be the main producer of phosphatidylinositol-3-monophosphate, a lipid that controls intracellular vesicular trafficking
We created mice in which the kinase activity of Vps[34] was disabled in the germline, by the introduction of a kinase-inactivating point mutation in the DFG motif of the kinase domain, as we previously reported for other isoforms of PI3K15–20
H Liver i mg/dl/mg liver WT D761A/+. These findings show that heterozygous inactivation of Vps[34] enhances glucose tolerance and insulin sensitivity by reducing glucose production in the liver and stimulating glucose uptake in muscle

Summary

Introduction

Vps[34] PI3K is thought to be the main producer of phosphatidylinositol-3-monophosphate, a lipid that controls intracellular vesicular trafficking. Vps[34] converts the phosphatidylinositol (PI) membrane lipid to PI3P, which coordinates the localization and function of effector proteins containing PI3P-binding domains such as FYVE, PX, or the FRRG domain found in PROPPINS, thereby controlling PI3P-mediated intracellular vesicular trafficking[3]. This includes (1) the earliest steps in the autophagy process where PI3P generation is a key event in autophagosome biogenesis, as well as later steps in autophagosome maturation, (2) endosomal maturation, and (3) phagocytosis[3]. To further model the pharmacological effect of kinase inhibition, which is most often incomplete in vivo, we focused on the study of mice with heterozygous inactivation of Vps[34]

Methods

Results

Conclusion