Abstract
BACKGROUND AND AIMS: Long term physical inactivity induces obesity and lead to insulin resistance. We have recently demonstrated that only 24 hours physical inactivity by leg immobilization induces insulin resistance in murine skeletal muscle. To elucidate its mechanism, we performed hind-limb cast immobilization (HCI) for 24 hours in C57BL6J mice and investigated ex-vivo insulin-stimulated 2-deoxy glucose uptake, insulin signal transduction and lipid composition in soleus muscle. RESULTS: Twenty-four hours HCI significantly decreased insulin-stimulated 2-deoxy glucose uptake by 41%. In parallel with this change, we observed decreased insulin stimulated serine phosphorylation of Akt and tyrosine phosphorylation of insulin receptor substrate (IRS)-1 after 24h HCI. It has been hypothesized that intramyocellular diacylglycerol (IMDG) accumulation and PKC activation impairs insulin signal transduction. Consistent with this hypothesis, we found that 24h HCI dramatically increased IMDG by 192%, while the amount of intramyocellular triacylglycerol (IMTG) was not changed. In addition, we also observed increase of PKCe translocation to the plasma membrane after 24 HCI. Associated with the IMDG accumulation, expression level of diacylglycerol acyltransferase (DGAT)-1, which converts diacylglycerol to triacylglycerol, was decreased by 53%, and activity of Lipin1, which converts phosphatidic acid to diacylglycerol, was increased by 141% after 24h HCI. Finally, overexpression of dominant negative Lipin1 in soleus muscle partially inhibited diacylglycerol accumulation after 24h HCI. CONCLUSION: These data suggested that 24h HCI induce insulin resistance through IMDG accumulation and trans-location of PKCe to the plasma membrane in skeletal muscle. Given that increased Lipin1 activity and decreased DGAT-1 expression might be involved in the mechanism of IMDG accumulation, suppression of lipin1 can be a drug target for insulin resistance induced by physical inactivity.
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