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 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
Subject
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
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