PMID- 17006666
OWN - NLM
STAT- MEDLINE
DCOM- 20070918
LR  - 20211203
IS  - 0012-186X (Print)
IS  - 0012-186X (Linking)
VI  - 49
IP  - 12
DP  - 2006 Dec
TI  - Sustained activation of the mammalian target of rapamycin nutrient sensing 
      pathway is associated with hepatic insulin resistance, but not with steatosis, in 
      mice.
PG  - 3049-57
AB  - 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 beta-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.
FAU - Korsheninnikova, E
AU  - Korsheninnikova E
AD  - Department of Molecular Cell Biology, Leiden University Medical Centre, Postzone 
      S1-P, Postbus 9600, 2300 RC, Leiden, The Netherlands. Elena@lumc.nl
FAU - van der Zon, G C M
AU  - van der Zon GC
FAU - Voshol, P J
AU  - Voshol PJ
FAU - Janssen, G M
AU  - Janssen GM
FAU - Havekes, L M
AU  - Havekes LM
FAU - Grefhorst, A
AU  - Grefhorst A
FAU - Kuipers, F
AU  - Kuipers F
FAU - Reijngoud, D-J
AU  - Reijngoud DJ
FAU - Romijn, J A
AU  - Romijn JA
FAU - Ouwens, D M
AU  - Ouwens DM
FAU - Maassen, J A
AU  - Maassen JA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20060928
PL  - Germany
TA  - Diabetologia
JT  - Diabetologia
JID - 0006777
RN  - 0 (Blood Glucose)
RN  - 0 (DNA, Mitochondrial)
RN  - 0 (Dietary Fats)
RN  - 0 (Fatty Acids)
RN  - 0 (Insulin)
RN  - 0 (Ribosomal Proteins)
RN  - EC 1.9.3.1 (Electron Transport Complex IV)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - GMW67QNF9C (Leucine)
SB  - IM
MH  - Animals
MH  - Blood Glucose/metabolism
MH  - DNA, Mitochondrial/genetics
MH  - Dietary Fats
MH  - Electron Transport Complex IV/genetics/metabolism
MH  - Fatty Acids/metabolism
MH  - Fatty Liver/*physiopathology
MH  - Insulin/blood
MH  - *Insulin Resistance
MH  - Leucine/blood
MH  - Liver/*physiology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphorylation
MH  - Protein Kinases/*physiology
MH  - Ribosomal Proteins/genetics
MH  - TOR Serine-Threonine Kinases
EDAT- 2006/09/29 09:00
MHDA- 2007/09/19 09:00
CRDT- 2006/09/29 09:00
PHST- 2006/05/10 00:00 [received]
PHST- 2006/07/24 00:00 [accepted]
PHST- 2006/09/29 09:00 [pubmed]
PHST- 2007/09/19 09:00 [medline]
PHST- 2006/09/29 09:00 [entrez]
AID - 10.1007/s00125-006-0439-5 [doi]
PST - ppublish
SO  - Diabetologia. 2006 Dec;49(12):3049-57. doi: 10.1007/s00125-006-0439-5. Epub 2006 
      Sep 28.