Print Email Facebook Twitter Sustained activation of the mammalian target of rapamycin nutrient sensing pathway is associated with hepatic insulin resistance, but not with steatosis, in mice Title Sustained activation of the mammalian target of rapamycin nutrient sensing pathway is associated with hepatic insulin resistance, but not with steatosis, in mice Author Korsheninnikova, E. van der Zon, G.C.M. Voshol, P.J. Janssen, G.M. Havekes, L.M. Grefhorst, A. Kuipers, F. Reijngoud, D.-J. Romijn, J.A. Ouwens, D.M. Maassen, J.A. TNO Kwaliteit van Leven Publication year 2006 Abstract Aims/hypothesis: Activation of nutrient sensing through mammalian target of rapamycin (mTOR) has been linked to the pathogenesis of insulin resistance. We examined activation of mTOR-signalling in relation to insulin resistance and hepatic steatosis in mice. Materials and methods: Chronic hepatic steatosis and hepatic insulin resistance were induced by high-fat feeding of male C57BL/6Jico mice for 6 weeks. In addition, acute hepatic steatosis in the absence of insulin resistance was induced by pharmacological blockade of β-oxidation using tetradecylglycidic acid (TDGA). mTOR signalling was examined in liver homogenates. Results: High-fat feeding caused obesity (p<0.001), hepatic steatosis (p<0.05) and hepatic insulin resistance (p<0.05). The phosphorylation of mTOR and its downstream targets p70S6 kinase and S6 ribosomal protein was two-fold higher in mice on a high-fat diet than in mice fed standard chow (all p<0.05) and associated with enhanced rates of protein synthesis. Acute induction of hepatic steatosis with TDGA had no effect on mTOR activity. The increased activity of the mTOR pathway in livers from mice on a high-fat diet could not be ascribed to diet-induced alterations in known modulators of mTOR activity such as circulating plasma leucine levels, phosphorylation of protein kinase B and AMP-activated protein kinase, and changes in mitochondrial function. Conclusions/interpretation: High-fat diet induces increase of the mTOR nutrient sensing pathway in association with hepatic insulin resistance, but not with hepatic lipid accumulation as such. © 2006 Springer-Verlag. Chemicals / CAS: glucose, 50-99-7, 84778-64-3; hydroxymethylglutaryl coenzyme A reductase kinase, 172522-01-9, 72060-32-3; insulin, 9004-10-8; protein kinase B, 148640-14-6; 1-Phosphatidylinositol 3-Kinase, EC 22.214.171.124; Blood Glucose; Dietary Fats; DNA, Mitochondrial; Electron Transport Complex IV, EC 126.96.36.199; Fatty Acids; Insulin, 11061-68-0; Leucine, 61-90-5; mTOR protein, EC 2.7.1.-; Protein Kinases, EC 188.8.131.52; Ribosomal Proteins Subject BiologyBiomedical ResearchHepatic steatosisHigh-fat feedingNutrient sensingEnzyme inhibitorGlucoseHydroxymethylglutaryl coenzyme A reductase kinaseMammalian target of rapamycinProtein kinase BProtein S6S6 kinaseTetradecylglycidic acidUnclassified drugAnimal experimentAnimal modelAnimal tissueControlled studyDiabetic obesityDiabetogenesisEnzyme activationGlucose clamp techniqueHyperinsulinemiaInsulin resistanceLipid dietLiver homogenateLiver mitochondrionMitochondrial membraneNonhumanNutrient concentrationNutrient contentProtein blood levelProtein inductionProtein phosphorylationProtein synthesisProtein targetingSpecies comparison1-Phosphatidylinositol 3-KinaseAnimalsBlood GlucoseDietary FatsDNA, MitochondrialElectron Transport Complex IVFatty AcidsFatty LiverInsulinInsulin ResistanceLeucineLiverMaleMiceMice, Inbred C57BLPhosphorylationProtein KinasesRibosomal Proteins To reference this document use: http://resolver.tudelft.nl/uuid:7ae3c375-231a-495f-b74a-df4d4f3bc043 DOI https://doi.org/10.1007/s00125-006-0439-5 TNO identifier 239621 ISSN 0012-186X Source Diabetologia, 49 (12), 3049-3057 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.