Cardiac diacylglycerol accumulation in high fat-fed mice is associated with impaired insulin-stimulated glucose oxidation

Aims The molecular processes leading to cardiac insulin resistance induced via a high-fat diet (HFD) remain unclear. We examined the changes in cardiac insulin sensitivity and the potential mechanism(s) involved following HFD in mice. Methods and results C57BL/6 mice were fed either a low-fat diet (LFD, 4% kcal fat) or a HFD (60% kcal fat) for 3 or 10 weeks. Insulin-stimulated glucose oxidation in isolated working hearts was decreased at 10 weeks of HFD compared with mice on LFD (249 +/- 19 to 399 +/- 46 vs. 551 +/- 97 to 1464 +/- 243 nmol/g dry wt/min; P < 0.05). The accumulation of myocardial diacylglycerol (DAG; 479 +/- 174 vs. 266 +/- 29 mu mol/g wet wt; P < 0.05), but not long-chain acyl CoA, ceramide, or triacylglycerol, correlated with the development of insulin resistance. The accumulation of DAG occurred concomitantly with an increase in glycerol phosphate acyltransferase activity, a decrease in DAG acyltransferase activity, as well as an increase in the translocation of protein kinase C-alpha (PKC alpha) and phosphorylation of p70s6k. Neither HFD-induced accumulation of cardiac DAG nor up-regulation of phosphorylated p70s6k occurred in mice lacking malonyl CoA decarboxylase which are resistant to the development of HFD-induced insulin resistance. Conclusion The activation of myocardial p70s6k and PKC alpha is closely associated with cardiac insulin resistance in which the accumulation of intra-myocardial DAG could be responsible.