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


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 micromol/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-α (PKCα) 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.


CONCLUSIONS
the activation of myocardial p70s6k and PKCα is closely associated with cardiac insulin resistance in which the accumulation of intra-myocardial DAG could be responsible.
Zhang
Liyan
L
Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, 423 Heritage Medical Research Center, Edmonton, AB, Canada T6G 2S2.
Ussher
John R
JR
Oka
Tatsujiro
T
Cadete
Virgilio J J
VJ
Wagg
Cory
C
Lopaschuk
Gary D
GD
D000214:Acyl Coenzyme A / Q000378:metabolism; D000818:Animals; D002262:Carboxy-Lyases / Q000172:deficiency / Q000235:genetics; D004041:Dietary Fats / Q000008:administration & dosage* / Q000009:adverse effects; D004075:Diglycerides / Q000378:metabolism*; D004734:Energy Metabolism / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D006321:Heart / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008066:Lipolysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008955:Models, Cardiovascular; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D010766:Phosphorylation; D051571:Protein Kinase C-alpha / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism
D000214:Acyl Coenzyme A; D004041:Dietary Fats; D004075:Diglycerides; D007328:Insulin; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D051571:Protein Kinase C-alpha; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase; D005947:Glucose