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Vps34 PI 3-kinase inactivation enhances insulin sensitivity through reprogramming of mitochondrial metabolism.
Bilanges, Benoit; Alliouachene, Samira; Pearce, Wayne; Morelli, Daniele; Szabadkai, Gyorgy; Chung, Yuen-Li; Chicanne, Gaëtan; Valet, Colin; Hill, Julia M; Voshol, Peter J; Collinson, Lucy; Peddie, Christopher; Ali, Khaled; Ghazaly, Essam; Rajeeve, Vinothini; Trichas, Georgios; Srinivas, Shankar; Chaussade, Claire; Salamon, Rachel S; Backer, Jonathan M; Scudamore, Cheryl L; Whitehead, Maria A; Keaney, Erin P; Murphy, Leon O; Semple, Robert K; Payrastre, Bernard; Tooze, Sharon A; Vanhaesebroeck, Bart.
Afiliação
  • Bilanges B; UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6DD, UK. b.bilanges@ucl.ac.uk.
  • Alliouachene S; UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6DD, UK.
  • Pearce W; UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6DD, UK.
  • Morelli D; UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6DD, UK.
  • Szabadkai G; Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, Gower Street, London, WC1E 6BT, UK.
  • Chung YL; Department of Biomedical Sciences, University of Padua, Padua, 58/B via Ugo, Bassi, 35121, Italy.
  • Chicanne G; Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research London, 123 Old Brompton Road, London, SW7 3RP, UK.
  • Valet C; Inserm/UPS UMR 1048, Institut des Maladies Métaboliques et Cardiovasculaires, 1 Avenue Jean Poulhès BP 84225, 31432, Toulouse Cedex 4, France.
  • Hill JM; Inserm/UPS UMR 1048, Institut des Maladies Métaboliques et Cardiovasculaires, 1 Avenue Jean Poulhès BP 84225, 31432, Toulouse Cedex 4, France.
  • Voshol PJ; Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, Gower Street, London, WC1E 6BT, UK.
  • Collinson L; Metabolic Research Laboratories, MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Level 4, Box 289, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
  • Peddie C; The Francis Crick Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London, WC2A 3LY, UK.
  • Ali K; The Francis Crick Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London, WC2A 3LY, UK.
  • Ghazaly E; UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6DD, UK.
  • Rajeeve V; Centre of Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK.
  • Trichas G; Centre of Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK.
  • Srinivas S; Department of Physiology Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK.
  • Chaussade C; Department of Physiology Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK.
  • Salamon RS; UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6DD, UK.
  • Backer JM; Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, 10461, NY, USA.
  • Scudamore CL; Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, 10461, NY, USA.
  • Whitehead MA; Mary Lyon Centre, MRC Harwell, Harwell Science and Innovation Campus, Harwell, OX11 0RD, UK.
  • Keaney EP; UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6DD, UK.
  • Murphy LO; Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, MA, 02139, USA.
  • Semple RK; Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, MA, 02139, USA.
  • Payrastre B; Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
  • Tooze SA; Inserm/UPS UMR 1048, Institut des Maladies Métaboliques et Cardiovasculaires, 1 Avenue Jean Poulhès BP 84225, 31432, Toulouse Cedex 4, France.
  • Vanhaesebroeck B; The Francis Crick Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London, WC2A 3LY, UK.
Nat Commun ; 8(1): 1804, 2017 11 27.
Article em En | MEDLINE | ID: mdl-29180704
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Resistência à Insulina / Transdução de Sinais / Fosfatidilinositol 3-Quinases / Mitocôndrias Tipo de estudo: Diagnostic_studies Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2017 Tipo de documento: Article
Texto completo
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XML
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Resistência à Insulina / Transdução de Sinais / Fosfatidilinositol 3-Quinases / Mitocôndrias Tipo de estudo: Diagnostic_studies Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2017 Tipo de documento: Article