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OBJECTIVE - Diet-induced obesity (DIO) leads to an accumulation of intra-myocardial fatty acid metabolites that have been proposed to cause myocardial insulin resistance and dysfunction. Our goal was to determine the effect of DIO on myocardial fatty acid metabolite accumulation and how this is altered when mitochondrial fatty acid uptake is inhibited. This was achieved by using mice lacking malonyl CoA decarboxylase (MCD−/−), which have higher levels of malonyl CoA, an endogenous inhibitor of mitochondrial fatty acid uptake. METHODS - Wild type (WT) and MCD−/− mice were fed a low (4% kcal from lard) or high (60% kcal from lard) fat diet for 12 weeks to determine the effect of DIO on the intra-myocardial accumulation of long chain acylcarnitines, long chain acyl CoAs, triglycerides (TGs), and ceramides. A parallel feeding study was performed to assess myocardial function and energy metabolism in isolated working hearts in the absence/presence of insulin. RESULTS - We demonstrate that MCD−/− mice do not accumulate intramyocardial long chain acylcarnitines to the same extent as WT mice following DIO (0.56 ± 0.10 vs. 0.28 ± 0.07 pmol myristoylcarnitine/mg protein, P <0.05), but do accumulate similar amounts of long chain acyl CoAs (3.88 ± 0.34 vs. 4.35 ± 1.19 nmol/g wet weight). Interestingly, DIO only lead to an accumulation of TGs in the hearts of MCD−/− mice (3.29 ± 0.62 vs. 10.92 ± 3.72 μmol/g wet weight, P <0.05). Despite this elevation in TGs, MCD−/− mice showed increased insulin-stimulated glucose oxidation (2.46 ± 0.25 vs. 1.74 ± 0.18 fold increase, P <0.05) during aerobic isolated working heart perfusions and did not elicit any dysfunction. CONCLUSIONS - Our data reveal discordance between myocardial TG accumulation and glucose metabolism, suggesting that TG buffers against toxic lipids, and that inhibition of mitochondrial fatty acid oxidation does not cause myocardial dysfunction following DIO.