Insulin-stimulated cardiac glucose oxidation is increased in high-fat diet-induced obese mice lacking malonyl CoA decarboxylase.
OBJECTIVE
Whereas an impaired ability to oxidize fatty acids is thought to contribute to intracellular lipid accumulation, insulin resistance, and cardiac dysfunction, high rates of fatty acid oxidation could also impair glucose metabolism and function. We therefore determined the effects of diet-induced obesity (DIO) in wild-type (WT) mice and mice deficient for malonyl CoA decarboxylase (MCD(-/-); an enzyme promoting mitochondrial fatty acid oxidation) on insulin-sensitive cardiac glucose oxidation.


METHODS
WT and MCD(-/-) mice were fed a low- or high-fat diet for 12 weeks, and intramyocardial lipid metabolite accumulation was assessed. A parallel feeding study was performed to assess myocardial function and energy metabolism (nanomoles per gram of dry weight per minute) in isolated working hearts (+/- insulin).


RESULTS
DIO markedly reduced insulin-stimulated glucose oxidation compared with low fat-fed WT mice (167 +/- 31 vs. 734 +/- 125; P < 0.05). MCD(-/-) mice subjected to DIO displayed a more robust insulin-stimulated glucose oxidation (554 +/- 82 vs. 167 +/- 31; P < 0.05) and less incomplete fatty acid oxidation, evidenced by a decrease in long-chain acylcarnitines compared with WT counterparts. MCD(-/-) mice had long-chain acyl CoAs similar to those of WT mice subjected to DIO but had increased triacylglycerol levels (10.92 +/- 3.72 vs. 3.29 +/- 0.62 mumol/g wet wt; P < 0.05).


CONCLUSIONS
DIO does not impair cardiac fatty acid oxidation or function, and there exists disassociation between myocardial lipid accumulation and insulin sensitivity. Our results suggest that MCD deficiency is not detrimental to the heart in obesity.
Ussher
John R
JR
Cardiovascular Research Group, University of Alberta, Edmonton, Canada.
Koves
Timothy R
TR
Jaswal
Jagdip S
JS
Zhang
Liyan
L
Ilkayeva
Olga
O
Dyck
Jason R B
JR
Muoio
Deborah M
DM
Lopaschuk
Gary D
GD
D000818:Animals; D002262:Carboxy-Lyases / Q000172:deficiency*; D004041:Dietary Fats / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D006321:Heart / Q000187:drug effects; D007328:Insulin / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D009206:Myocardium / Q000378:metabolism*
D004041:Dietary Fats; D007328:Insulin; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase; D005947:Glucose