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Insulin-stimulated cardiac glucose oxidation is increased in high-fat diet-induced obese mice lacking malonyl CoA decarboxylase.

Ussher JR, Koves TR, Jaswal JS, Zhang L, Ilkayeva O, Dyck JR, Muoio DM, Lopaschuk GD - Diabetes (2009)

Bottom Line: DIO markedly reduced insulin-stimulated glucose oxidation compared with low fat-fed WT mice (167 +/- 31 vs. 734 +/- 125; P < 0.05).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.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Research Group, University of Alberta, Edmonton, Canada.

ABSTRACT

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.

Research design and 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.

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Related in: MedlinePlus

Improvement of insulin senstivity in MCD−/− mice subjected to DIO does not correlate with the accumulation of myocardial lipid intermediates. A: DIO increased long-chain acyl CoAs to similar extents in both WT and MCD−/− mice. B: Triacylglycerols only accumulated in MCD−/− mice following DIO and did not accumulate in WT mice. C: Ceramides do not accumulate following DIO in hearts from WT and MCD−/− mice. Values represent means ± SE (n = 4–11). Differences were determined using a two-way ANOVA followed by Bonferroni post hoc analysis. *P < 0.05, significantly different from low fat–fed counterpart. ■, MCD−/−; □, WT.
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Figure 5: Improvement of insulin senstivity in MCD−/− mice subjected to DIO does not correlate with the accumulation of myocardial lipid intermediates. A: DIO increased long-chain acyl CoAs to similar extents in both WT and MCD−/− mice. B: Triacylglycerols only accumulated in MCD−/− mice following DIO and did not accumulate in WT mice. C: Ceramides do not accumulate following DIO in hearts from WT and MCD−/− mice. Values represent means ± SE (n = 4–11). Differences were determined using a two-way ANOVA followed by Bonferroni post hoc analysis. *P < 0.05, significantly different from low fat–fed counterpart. ■, MCD−/−; □, WT.

Mentions: It has been suggested that an impairment in the mitochondrial uptake and subsequent oxidation of fatty acids contribute to the accumulation of intramuscular acyl CoAs and the development of insulin resistance (6,8,15) and myocardial dysfunction (16,17,20). Therefore, we investigated the effects of DIO on the myocardial accumulation of acyl CoAs. In low fat–fed mice, MCD deficiency did not alter the levels of the major long-chain acyl CoAs or total long-chain acyl CoAs compared with those in WT mice (Fig. 5A). DIO resulted in a marked increase in the major cardiac long-chain acyl CoAs and total long-chain acyl CoAs in WT mice compared with low fat–fed mice (Fig. 4A). DIO significantly increased intramyocardial long-chain acyl CoA levels to similar extents in MCD−/− mice compared with WT mice (Fig. 5A). This demonstrates dissociation between long-chain acyl CoA accumulation and insulin sensitivity in DIO mice.


Insulin-stimulated cardiac glucose oxidation is increased in high-fat diet-induced obese mice lacking malonyl CoA decarboxylase.

Ussher JR, Koves TR, Jaswal JS, Zhang L, Ilkayeva O, Dyck JR, Muoio DM, Lopaschuk GD - Diabetes (2009)

Improvement of insulin senstivity in MCD−/− mice subjected to DIO does not correlate with the accumulation of myocardial lipid intermediates. A: DIO increased long-chain acyl CoAs to similar extents in both WT and MCD−/− mice. B: Triacylglycerols only accumulated in MCD−/− mice following DIO and did not accumulate in WT mice. C: Ceramides do not accumulate following DIO in hearts from WT and MCD−/− mice. Values represent means ± SE (n = 4–11). Differences were determined using a two-way ANOVA followed by Bonferroni post hoc analysis. *P < 0.05, significantly different from low fat–fed counterpart. ■, MCD−/−; □, WT.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2712785&req=5

Figure 5: Improvement of insulin senstivity in MCD−/− mice subjected to DIO does not correlate with the accumulation of myocardial lipid intermediates. A: DIO increased long-chain acyl CoAs to similar extents in both WT and MCD−/− mice. B: Triacylglycerols only accumulated in MCD−/− mice following DIO and did not accumulate in WT mice. C: Ceramides do not accumulate following DIO in hearts from WT and MCD−/− mice. Values represent means ± SE (n = 4–11). Differences were determined using a two-way ANOVA followed by Bonferroni post hoc analysis. *P < 0.05, significantly different from low fat–fed counterpart. ■, MCD−/−; □, WT.
Mentions: It has been suggested that an impairment in the mitochondrial uptake and subsequent oxidation of fatty acids contribute to the accumulation of intramuscular acyl CoAs and the development of insulin resistance (6,8,15) and myocardial dysfunction (16,17,20). Therefore, we investigated the effects of DIO on the myocardial accumulation of acyl CoAs. In low fat–fed mice, MCD deficiency did not alter the levels of the major long-chain acyl CoAs or total long-chain acyl CoAs compared with those in WT mice (Fig. 5A). DIO resulted in a marked increase in the major cardiac long-chain acyl CoAs and total long-chain acyl CoAs in WT mice compared with low fat–fed mice (Fig. 4A). DIO significantly increased intramyocardial long-chain acyl CoA levels to similar extents in MCD−/− mice compared with WT mice (Fig. 5A). This demonstrates dissociation between long-chain acyl CoA accumulation and insulin sensitivity in DIO mice.

Bottom Line: DIO markedly reduced insulin-stimulated glucose oxidation compared with low fat-fed WT mice (167 +/- 31 vs. 734 +/- 125; P < 0.05).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.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Research Group, University of Alberta, Edmonton, Canada.

ABSTRACT

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.

Research design and 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.

Show MeSH
Related in: MedlinePlus