Mechanisms of S6K1 Mediated Insulin Resistance

Summary

Principal Investigator: George Thomas
Abstract: The molecular mechanisms by which obesity leads to impaired insulin action are not well understood. However, recent studies, particularly in mice deficient for key components of the insulin-signaling pathway, have begun to provide molecular insights and potential models to study the role of obesity in the development of type 2 diabetes. Here we provide preliminary data in the mouse, showing that one such component, ribosomal protein S6 kinase 1 (S6K1), plays not only a positive role in insulin-induced anabolic responses associated with cell growth, but also a negative role. This negative role is revealed under conditions of nutrient satiation and is most likely mediated through the phosphorylation of specific residues on insulin receptor substrate 1 (IRS1). Phosphorylation at these sites is known to dampen phosphatidylinositide-3OH kinase (PI3K) binding to IRS1, reduce glucose uptake and lead to insulin resistance. However, the sites of phosphorylated in IRS1 are not S6K1 phosphorylation sites, but sites regulated by the mammalian Target Of Rapamycin (mTOR) an immediate upstream kinase involved in the phosphorylation and activation of S6K1. Our hypothesis is that nutrient activation of S6K1 negatively regulates insulin action by promoting mTOR phosphorylation of IRS1, leading to insulin resistance. Our research plan is to (i) identify the IRS1 phosphorylation sites mediated by mTOR, (ii) determine the mechanism by which absence of S6K1 reduces IRS1 phosphorylation by mTOR, and (iii) measure the extent to which S6K1 contributes to the development of diet-induced insulin resistance in the mouse. Given that nutrient satiation drives S6K1 activation and is intimately associated with obesity and insulin resistance, it is important to determine the extent to which S6K1 contributes to these pathologies. Obesity has become a worldwide epidemic, not only leading to type 2 diabetes, but is also a major cause of cancer and cardiovascular deaths. This epidemic has arisen because of the dramatic rise in food intake, which is due to the fact that food is abundant, tasteful, and inexpensive. That man was a scavenger until recent times has accentuated this effect, such that genetic traits to secure and retain food have prevailed over those that suppressed food intake. Thus, if S6K1 is a critical player in these diseases the development of a small molecule inhibitor to S6K1 may act to improve the quality of life of those suffering from insulin resistance.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi hvps34, an ancient player, enters a growing game: mTOR Complex1/S6K1 signaling
    Takahiro Nobukuni
    Genome Research Institute, University of Cincinnati, 2180 E Galbraith Rd, Cincinnati, OH 45237, USA
    Curr Opin Cell Biol 19:135-41. 2007
  2. ncbi mTOR Complex1-S6K1 signaling: at the crossroads of obesity, diabetes and cancer
    Stephen G Dann
    Genome Research Institute, University of Cincinnati, 2180 E Galbraith Road, Cincinnati, OH 45237, USA
    Trends Mol Med 13:252-9. 2007
  3. pmc Identification of IRS-1 Ser-1101 as a target of S6K1 in nutrient- and obesity-induced insulin resistance
    Frederic Tremblay
    Department of Anatomy and Physiology, Laval University Hospital Research Center, Ste Foy, QC, Canada G1V 4G2
    Proc Natl Acad Sci U S A 104:14056-61. 2007
  4. ncbi Identifying optimal biologic doses of everolimus (RAD001) in patients with cancer based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data
    Chiaki Tanaka
    Novartis Pharmaceuticals Corp, East Hanover, NJ, USA
    J Clin Oncol 26:1596-602. 2008
  5. pmc Amino acids activate mTOR complex 1 via Ca2+/CaM signaling to hVps34
    Pawan Gulati
    Department of Molecular Oncogenesis, Genome Research Institute, University of Cincinnati, Cincinnati, OH 45237, USA
    Cell Metab 7:456-65. 2008
  6. pmc mTORC1-mediated cell proliferation, but not cell growth, controlled by the 4E-BPs
    Ryan J O Dowling
    Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3A 1A3, Canada
    Science 328:1172-6. 2010
  7. pmc S6K1 plays a critical role in early adipocyte differentiation
    Larissa S Carnevalli
    Department of Cancer and Cell Biology, Metabolic Diseases Institute, College of Medicine, University of Cincinnati, Cincinnati, OH 45237, USA
    Dev Cell 18:763-74. 2010
  8. pmc The nuclear receptor DHR3 modulates dS6 kinase-dependent growth in Drosophila
    Jacques Montagne
    Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
    PLoS Genet 6:e1000937. 2010
  9. pmc Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner
    Adem Kalender
    Department of Cancer and Cell Biology, Metabolic Diseases Institute, University of Cincinnati, 2180 E Galbraith Road, Cincinnati, OH 45237, USA
    Cell Metab 11:390-401. 2010
  10. pmc S6K1 deficiency protects against apoptosis in hepatocytes
    Agueda Gonzalez-Rodriguez
    Instituto de Investigaciones Biomedicas Alberto Sols CSIC UAM, c Arturo Duperier 4, 28029 Madrid, Spain
    Hepatology 50:216-29. 2009

Scientific Experts

  • Jacques Montagne
  • George Thomas
  • Sara C Kozma
  • Sung Hee Um
  • Anand Selvaraj
  • Pawan Gulati
  • Takahiro Nobukuni
  • Stephen G Dann
  • Tamara R Castaneda
  • Larissa S Carnevalli
  • Nahum Sonenberg
  • Ivan Topisirovic
  • Adem Kalender
  • Ryan J O Dowling
  • Agueda Gonzalez-Rodriguez
  • Sophie Brûlé
  • Andre Marette
  • Chiaki Tanaka
  • Frederic Tremblay
  • David Y Hui
  • William Abplanalp
  • Erin Grant
  • Paul T Pfluger
  • Stephen C Benoit
  • Brigitte Schrott
  • Larissa Carnevalli
  • Kamal Rahmouni
  • Matthias H Tschop
  • Donald A Morgan
  • Deborah J Clegg
  • Kimberly Brown
  • Dean Gilham
  • Nabeel Bardeesy
  • Yi Liu
  • Bruno D Fonseca
  • Kouhei Masuda
  • Bruce E Kemp
  • Ola Larsson
  • Tommy Alain
  • Patrick Dennis
  • Valentina Gandin
  • Emmanuel Petroulakis
  • Xiaoshan Wang
  • John J Schlager
  • Olivier Le Bacquer
  • So Young Kim
  • Francesca Frigerio
  • Benoit Viollet
  • Michael Bidinosti
  • Valeri Zimmerman
  • Angela M Valverde
  • Javier Alba
  • Heidi A Lane
  • Nicholas Shand
  • Sabine Zumstein-Mecker
  • Manel Joaquin
  • Lawrence D Gaspers
  • Andrew P Thomas
  • Eric Raymond
  • Katharine Hazell
  • Christine Stephan
  • Marc Hattenberger
  • Francois Natt
  • Terence O'Reilly
  • Anne Boulay
  • Ian Judson
  • John M Kovarik
  • Michael Roden
  • Xiao Jian Sun
  • Michael Krebs
  • Roberto D Polakiewicz
  • Yu Li
  • Kohei Masuda

Detail Information

Publications12

  1. ncbi hvps34, an ancient player, enters a growing game: mTOR Complex1/S6K1 signaling
    Takahiro Nobukuni
    Genome Research Institute, University of Cincinnati, 2180 E Galbraith Rd, Cincinnati, OH 45237, USA
    Curr Opin Cell Biol 19:135-41. 2007
    ..These functions of hVps34 initially appear contradictory, since increased mTOR Complex1 activation is triggered by increased amino acid levels, while autophagy is triggered when cells are faced with amino acid deprivation...
  2. ncbi mTOR Complex1-S6K1 signaling: at the crossroads of obesity, diabetes and cancer
    Stephen G Dann
    Genome Research Institute, University of Cincinnati, 2180 E Galbraith Road, Cincinnati, OH 45237, USA
    Trends Mol Med 13:252-9. 2007
    ..Thus, to orchestrate the control of homeostatic responses, mTOR Complex1 must integrate signals from distinct cues. Here, we review recent findings concerning the regulation and pathophysiology associated with mTOR Complex1 and S6K1...
  3. pmc Identification of IRS-1 Ser-1101 as a target of S6K1 in nutrient- and obesity-induced insulin resistance
    Frederic Tremblay
    Department of Anatomy and Physiology, Laval University Hospital Research Center, Ste Foy, QC, Canada G1V 4G2
    Proc Natl Acad Sci U S A 104:14056-61. 2007
    ..These findings indicate that nutrient- and hormonal-dependent activation of S6K1 causes insulin resistance in mice and humans, in part, by mediating IRS-1 Ser-1101 phosphorylation...
  4. ncbi Identifying optimal biologic doses of everolimus (RAD001) in patients with cancer based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data
    Chiaki Tanaka
    Novartis Pharmaceuticals Corp, East Hanover, NJ, USA
    J Clin Oncol 26:1596-602. 2008
    ....
  5. pmc Amino acids activate mTOR complex 1 via Ca2+/CaM signaling to hVps34
    Pawan Gulati
    Department of Molecular Oncogenesis, Genome Research Institute, University of Cincinnati, Cincinnati, OH 45237, USA
    Cell Metab 7:456-65. 2008
    ..These findings have important implications regarding the basic signaling mechanisms linking metabolic disorders with cancer progression...
  6. pmc mTORC1-mediated cell proliferation, but not cell growth, controlled by the 4E-BPs
    Ryan J O Dowling
    Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3A 1A3, Canada
    Science 328:1172-6. 2010
    ..Thus, control of cell size and cell cycle progression appear to be independent in mammalian cells, whereas in lower eukaryotes, 4E-BPs influence both cell growth and proliferation...
  7. pmc S6K1 plays a critical role in early adipocyte differentiation
    Larissa S Carnevalli
    Department of Cancer and Cell Biology, Metabolic Diseases Institute, College of Medicine, University of Cincinnati, Cincinnati, OH 45237, USA
    Dev Cell 18:763-74. 2010
    ..These results led to the conclusion that a lack of S6K1 impairs the generation of de novo adipocytes when mice are challenged with a HFD, consistent with a reduction in early adipocyte progenitors...
  8. pmc The nuclear receptor DHR3 modulates dS6 kinase-dependent growth in Drosophila
    Jacques Montagne
    Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
    PLoS Genet 6:e1000937. 2010
    ..These results provide the first molecular link between the dS6K pathway, critical in controlling nutrient-dependent growth, and that of DHR3, a major mediator of ecdysone signaling, which, acting together, coordinate metamorphosis...
  9. pmc Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner
    Adem Kalender
    Department of Cancer and Cell Biology, Metabolic Diseases Institute, University of Cincinnati, 2180 E Galbraith Road, Cincinnati, OH 45237, USA
    Cell Metab 11:390-401. 2010
    ..We found that the ability of biguanides to inhibit mTORC1 activation and signaling is, instead, dependent on the Rag GTPases...
  10. pmc S6K1 deficiency protects against apoptosis in hepatocytes
    Agueda Gonzalez-Rodriguez
    Instituto de Investigaciones Biomedicas Alberto Sols CSIC UAM, c Arturo Duperier 4, 28029 Madrid, Spain
    Hepatology 50:216-29. 2009
    ..However, S6K1(-/-) hepatocytes underwent apoptosis on serum withdrawal in combination with phosphatidylinositol 3-kinase (PI3K) or ERK inhibitors...
  11. pmc Metabolic control by S6 kinases depends on dietary lipids
    Tamara R Castaneda
    Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Dusseldorf, Germany
    PLoS ONE 7:e32631. 2012
    ..Taken together, our results suggest that the metabolic functions of S6K in vivo play a key role as a molecular interface connecting dietary lipids to the endogenous control of energy metabolism...