Abstract

Objective: While 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.

Research Design and Methods: WT and MCD−/− mice were fed a low fat or high fat diet for 12 weeks and intra-myocardial lipid metabolite accumulation was assessed. A parallel feeding study was performed to assess myocardial function and energy metabolism (nmol/g dry wt/min) in isolated working hearts (+/− insulin).

Results: DIO markedly reduced insulin-stimulated glucose oxidation compared to 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 displayed less incomplete fatty acid oxidation, evidenced by a decrease in long chain acylcarnitines compared to WT counterparts. MCD−/− had similar long chain acyl CoAs as WT mice subjected to DIO, but had increased triacylglycerol (TG) levels (10.92 ± 3.72 vs. 3.29 ± 0.62 μmol/g wet wt, P<0.05).

Conclusions: DIO does not impair cardiac fatty acid oxidation or function, and we demonstrate disassociation between myocardial lipid accumulation and insulin sensitivity. Our results suggest that MCD deficiency is not detrimental to the heart in obesity.