Exp Clin Endocrinol Diabetes 2006; 114 - OR5_26
DOI: 10.1055/s-2006-932864

A high fat diet induces insulin resistance and insulin-independent activation of the mTOR-S6 kinase pathway in mouse liver

E Korsheninnikova 1, GCM van der Zon 1, PJ Voshol 2, G Janssen 1, L Havekes 3, J Romijn 2, M Ouwens 1, JA Maassen 1
  • 1Leiden University Medical Center, Molecular Cell Biology, Leiden, Netherlands
  • 2Leiden University Medical Center, Department of Endocrinology, Leiden, Netherlands
  • 3Leiden University Medical Center, Department of Internal Medicine, Leiden, Netherlands

The objective of the study was to examine the effect of high fat diet on activation status of a number of signaling proteins that are potentially linked to insulin resistance and metabolic setting in mouse liver.

Methods: We have compared two groups of male C57BL/6Jico mice, one on a control chow diet (CH-mice, n=7) and the other on a high fat diet (HF-mice, n=7). High fat diet for 6 weeks caused a 16% increase in the body weight (P<0.001) and 25% increase in fasting plasma insulin (P=0.05). We show that the HF mice exhibit whole body insulin resistance under conditions of euglycemic hyperinsulinemic clamp (42% reduction in glucose infusion rate, P<0.05).

Results: First, we characterized insulin receptor (IR) signaling pathway (metabolic) in the liver in response to HF diet at the basal (insulin-independent) state. Surprisingly, no downregulation of the insulin receptor signaling pathway was observed in HF-mice: phosphorylation of IR, IR substrates 1 and 2, protein kinase B as well as IR substrate-1/2-associated phosphatidylinositol kinase activity were not significantly different between CH and HF groups. Secondly, we evaluated the mTor (nutrient) pathway in the liver of these animals. In the HF, insulin resistant animals at basal state a sustained activation of the mTor-S6 pathway: increased phosphorylation of mTor (0.5±0.1 vs. 1.1±0.1, P<0.01) and S6 kinase (1.3±0.2 vs. 2.6±0.5, P<0.05, CH vs. HF) was observed leading to increased protein synthetic activity in fatty liver. Phosphorylation of acetyl-CoA carboxylase (ACC) was 5 times higher in HF mice compared to CH as well as total protein level of ACC (P<0.05). Interestingly, AMPK phosphorylation that normally regulates mTor and ACC was not changed.

Conclusion: The mTor the pathway undergoes activation by a HF-diet that occurs independent of changes in activation of the insulin receptor metabolic pathway, AMPK activation and the number of mitochondria. This points to an additional, fatty acid-regulated sensor in the liver that excerts its action via the mTOR pathway.