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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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MCD deficiency improves insulin-stimulated glucose oxidation in DIO mice. A: DIO lead to an impairment in insulin-stimulated glucose oxidation in hearts from WT mice (□) that was prevented in hearts from MCD−/− mice (■). B: Rates of fatty acid oxidation did not differ in hearts from WT (□) and MCD−/− (■) mice. C: However, the contribution of myocardial fatty acid oxidation rates to acetyl CoA production was decreased in MCD−/− DIO versus WT DIO mice. □, Glucose oxidation; ■, fatty acid oxidation. Values represent means ± SE (n = 5–7). Differences were determined using a repeated-measures ANOVA. *P < 0.05, significantly different from low-fat counterpart. †P < 0.05, significantly different from insulin-negative counterpart. ‡P < 0.05, significantly different from insulin-positive high-fat WT.
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Figure 1: MCD deficiency improves insulin-stimulated glucose oxidation in DIO mice. A: DIO lead to an impairment in insulin-stimulated glucose oxidation in hearts from WT mice (□) that was prevented in hearts from MCD−/− mice (■). B: Rates of fatty acid oxidation did not differ in hearts from WT (□) and MCD−/− (■) mice. C: However, the contribution of myocardial fatty acid oxidation rates to acetyl CoA production was decreased in MCD−/− DIO versus WT DIO mice. □, Glucose oxidation; ■, fatty acid oxidation. Values represent means ± SE (n = 5–7). Differences were determined using a repeated-measures ANOVA. *P < 0.05, significantly different from low-fat counterpart. †P < 0.05, significantly different from insulin-negative counterpart. ‡P < 0.05, significantly different from insulin-positive high-fat WT.

Mentions: Subjecting mice to a 12-week period of DIO did not result in any alteration in isolated working heart function compared with low fat–fed mice (Table 1). Of interest is that cardiac function was also normal in MCD−/− mice regardless of whether they were obtained from the low fat–fed or DIO group. This demonstrates that MCD deficiency does not contribute to cardiac dysfunction in DIO mice. Reinforcing our ex vivo perfusion data, we also showed via ultrasound echocardiography that in vivo cardiac function was unaltered by DIO in WT or MCD−/− mice (Table 2). Despite the lack of functional changes, dramatic differences in cardiac energy metabolism were observed between the experimental groups. Hearts from WT mice subjected to DIO had a significant reduction in glucose oxidation rates compared with low fat–fed mice, with no change in oxidation of exogenously supplied [9,10-3H]palmitate (Fig. 1B). Insulin (100 μU/ml) robustly stimulated myocardial glucose oxidation in low fat–fed WT mice (Fig. 1A) and decreased fatty acid oxidation (Fig. 1B). In contrast, insulin had only a small effect on glucose oxidation in WT DIO mice (Table 3), demonstrating an impaired insulin-stimulated glucose metabolism in these DIO hearts.


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 improves insulin-stimulated glucose oxidation in DIO mice. A: DIO lead to an impairment in insulin-stimulated glucose oxidation in hearts from WT mice (□) that was prevented in hearts from MCD−/− mice (■). B: Rates of fatty acid oxidation did not differ in hearts from WT (□) and MCD−/− (■) mice. C: However, the contribution of myocardial fatty acid oxidation rates to acetyl CoA production was decreased in MCD−/− DIO versus WT DIO mice. □, Glucose oxidation; ■, fatty acid oxidation. Values represent means ± SE (n = 5–7). Differences were determined using a repeated-measures ANOVA. *P < 0.05, significantly different from low-fat counterpart. †P < 0.05, significantly different from insulin-negative counterpart. ‡P < 0.05, significantly different from insulin-positive high-fat WT.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 1: MCD deficiency improves insulin-stimulated glucose oxidation in DIO mice. A: DIO lead to an impairment in insulin-stimulated glucose oxidation in hearts from WT mice (□) that was prevented in hearts from MCD−/− mice (■). B: Rates of fatty acid oxidation did not differ in hearts from WT (□) and MCD−/− (■) mice. C: However, the contribution of myocardial fatty acid oxidation rates to acetyl CoA production was decreased in MCD−/− DIO versus WT DIO mice. □, Glucose oxidation; ■, fatty acid oxidation. Values represent means ± SE (n = 5–7). Differences were determined using a repeated-measures ANOVA. *P < 0.05, significantly different from low-fat counterpart. †P < 0.05, significantly different from insulin-negative counterpart. ‡P < 0.05, significantly different from insulin-positive high-fat WT.
Mentions: Subjecting mice to a 12-week period of DIO did not result in any alteration in isolated working heart function compared with low fat–fed mice (Table 1). Of interest is that cardiac function was also normal in MCD−/− mice regardless of whether they were obtained from the low fat–fed or DIO group. This demonstrates that MCD deficiency does not contribute to cardiac dysfunction in DIO mice. Reinforcing our ex vivo perfusion data, we also showed via ultrasound echocardiography that in vivo cardiac function was unaltered by DIO in WT or MCD−/− mice (Table 2). Despite the lack of functional changes, dramatic differences in cardiac energy metabolism were observed between the experimental groups. Hearts from WT mice subjected to DIO had a significant reduction in glucose oxidation rates compared with low fat–fed mice, with no change in oxidation of exogenously supplied [9,10-3H]palmitate (Fig. 1B). Insulin (100 μU/ml) robustly stimulated myocardial glucose oxidation in low fat–fed WT mice (Fig. 1A) and decreased fatty acid oxidation (Fig. 1B). In contrast, insulin had only a small effect on glucose oxidation in WT DIO mice (Table 3), demonstrating an impaired insulin-stimulated glucose metabolism in these DIO hearts.

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