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Sustained activation of the mammalian target of rapamycin nutrient sensing pathway is associated with hepatic insulin resistance, but not with steatosis, in mice

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Author: Korsheninnikova, E. · Zon, G.C.M. van der · 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.
Type:article
Date:2006
Institution: TNO Kwaliteit van Leven
Source:Diabetologia, 12, 49, 3049-3057
Identifier: 239621
doi: doi:10.1007/s00125-006-0439-5
Keywords: Biology · Biomedical Research · Hepatic steatosis · High-fat feeding · Nutrient sensing · Enzyme inhibitor · Glucose · Hydroxymethylglutaryl coenzyme A reductase kinase · Mammalian target of rapamycin · Protein kinase B · Protein S6 · S6 kinase · Tetradecylglycidic acid · Unclassified drug · Animal experiment · Animal model · Animal tissue · Controlled study · Diabetic obesity · Diabetogenesis · Enzyme activation · Glucose clamp technique · Hyperinsulinemia · Insulin resistance · Lipid diet · Liver homogenate · Liver mitochondrion · Mitochondrial membrane · Nonhuman · Nutrient concentration · Nutrient content · Protein blood level · Protein induction · Protein phosphorylation · Protein synthesis · Protein targeting · Species comparison · 1-Phosphatidylinositol 3-Kinase · Animals · Blood Glucose · Dietary Fats · DNA, Mitochondrial · Electron Transport Complex IV · Fatty Acids · Fatty Liver · Insulin · Insulin Resistance · Leucine · Liver · Male · Mice · Mice, Inbred C57BL · Phosphorylation · Protein Kinases · Ribosomal Proteins

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 2.7.1.137; Blood Glucose; Dietary Fats; DNA, Mitochondrial; Electron Transport Complex IV, EC 1.9.3.1; Fatty Acids; Insulin, 11061-68-0; Leucine, 61-90-5; mTOR protein, EC 2.7.1.-; Protein Kinases, EC 2.7.1.37; Ribosomal Proteins