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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

MCD deficiency increases myocardial malonyl CoA levels in DIO mice. Malonyl CoA levels were higher in MCD−/− (■) than WT (□) mice following low-fat diet or DIO. Values represent means ± SE (n = 4–5). Differences were determined using a two-way ANOVA followed by Bonferroni post hoc analysis. *P < 0.05, significantly different from diet-matched WT mice.
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Figure 3: MCD deficiency increases myocardial malonyl CoA levels in DIO mice. Malonyl CoA levels were higher in MCD−/− (■) than WT (□) mice following low-fat diet or DIO. Values represent means ± SE (n = 4–5). Differences were determined using a two-way ANOVA followed by Bonferroni post hoc analysis. *P < 0.05, significantly different from diet-matched WT mice.

Mentions: Because malonyl CoA is a major regulator of cardiac fatty acid oxidation, we examined what effect DIO had on cardiac malonyl CoA levels. Shown in Fig. 3, DIO had no effect on malonyl CoA levels in WT mice compared with low fat–fed WT mice. As expected, MCD−/− mice subjected to DIO showed a significant increase in malonyl CoA levels compared with WT DIO mice (Fig. 3). In addition, malonyl CoA levels from fasted WT mice did not differ from their fed counterparts but were significantly lower than those in fasted MCD−/− mice (supplemental Fig. 1A).


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)

MCD deficiency increases myocardial malonyl CoA levels in DIO mice. Malonyl CoA levels were higher in MCD−/− (■) than WT (□) mice following low-fat diet or DIO. Values represent means ± SE (n = 4–5). Differences were determined using a two-way ANOVA followed by Bonferroni post hoc analysis. *P < 0.05, significantly different from diet-matched WT mice.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 3: MCD deficiency increases myocardial malonyl CoA levels in DIO mice. Malonyl CoA levels were higher in MCD−/− (■) than WT (□) mice following low-fat diet or DIO. Values represent means ± SE (n = 4–5). Differences were determined using a two-way ANOVA followed by Bonferroni post hoc analysis. *P < 0.05, significantly different from diet-matched WT mice.
Mentions: Because malonyl CoA is a major regulator of cardiac fatty acid oxidation, we examined what effect DIO had on cardiac malonyl CoA levels. Shown in Fig. 3, DIO had no effect on malonyl CoA levels in WT mice compared with low fat–fed WT mice. As expected, MCD−/− mice subjected to DIO showed a significant increase in malonyl CoA levels compared with WT DIO mice (Fig. 3). In addition, malonyl CoA levels from fasted WT mice did not differ from their fed counterparts but were significantly lower than those in fasted MCD−/− mice (supplemental Fig. 1A).

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