@article{79dc48a56e1c4832863cc0439df6e492,
title = "Vps34 PI 3-kinase inactivation enhances insulin sensitivity through reprogramming of mitochondrial metabolism",
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.",
author = "Benoit Bilanges and Samira Alliouachene and Wayne Pearce and Daniele Morelli and Gyorgy Szabadkai and Chung, {Yuen Li} and Ga{\"e}tan Chicanne and Colin Valet and Hill, {Julia M.} and Voshol, {Peter J.} and Lucy Collinson and Christopher Peddie and Khaled Ali and Essam Ghazaly and Vinothini Rajeeve and Georgios Trichas and Shankar Srinivas and Claire Chaussade and Salamon, {Rachel S.} and Backer, {Jonathan M.} and Scudamore, {Cheryl L.} and Whitehead, {Maria A.} and Keaney, {Erin P.} and Murphy, {Leon O.} and Semple, {Robert K.} and Bernard Payrastre and Tooze, {Sharon A.} and Bart Vanhaesebroeck",
note = "Funding Information: We thank members from the Cell Signalling laboratory for discussions, Harald Stenmark (University of Oslo, Norway) for providing reagents, staff at TaconicArtemis (Cologne; Germany) for mouse gene targeting, Guillaume Halet (Rennes, France) for help with the blastocyst outgrowths, Remi Mounier (Lyon, France) for help with myoblast isolation and culture. and Zuncai Wang, Andrew Powers, Bryan Lafitte, and Brian Ethell (Novartis Institutes for BioMedical Research) for experiments to guide the in vivo use of compound 19. Postdoctoral fellowships were from EU Marie Curie (PIEF-GA-2009–252916) and EMBO (ALTF 753–2010) for SA and EU Marie Curie (PIIF-GA-2009–252846) for C.C. J. M.H. was a recipient of a doctoral fellowship from Eisai UK Ltd. Work in our laboratories was supported as follows: BV: MRC [G0700755], BBSRC (BB/I007806/1 and BB/ M013278/1), CRUK (C23338/A15965), the Ludwig Institute for Cancer Research and the National Institute for Health Research (NIHR) UCL Hospitals Biomedical Research Centre; J.M.B.: NIH AG039632, GM112524. and the Albert Einstein Diabetes Research and Training Center Animal Physiology Core DK020541; E.G.: Barry Reed Cancer Research fund; G.S.: BBSRC (BB/L020874/1) and B.H.F.; S.S.: Anatomical Society of Great Britain (GT) and a Wellcome Trust Career Development Fellowship 074246/Z04/Z (S.S.); R.K.S.: Wellcome Trust (WT098498) and M.R.C. (MRC_MC_UU_12012/5); S.A. T. and L.C.: the Francis Crick Institute, which receives its core funding from CRUK (FC001187), MRC (FC001187), and the Wellcome Trust (FC001187); Y.-L.C.: the CRUK Cancer Imaging Centre in association with the MRC and DoH (England) grant C1060/ A10334, C1060/A16464, NHS funding to the NIHR BRC; B.P.: Inserm and the Fondation pour la recherche m{\'e}dicale. B.P. is a scholar of the Institut Universitaire de France. Publisher Copyright: {\textcopyright} 2017 The Author(s).",
year = "2017",
month = dec,
day = "1",
doi = "10.1038/s41467-017-01969-4",
language = "English (US)",
volume = "8",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}
