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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

Neither DIO nor MCD deficiency alters the expression of proteins involved in energy metabolism and mitochondrial function. A: PGC1-α expression is not altered by DIO or MCD deficiency. B: UCP2 expression is not altered by DIO or MCD deficiency. Values represent means ± SE (n = 4 per group). ■, MCD−/−; □, WT. HF, high-fat diet; KO, knockout; LF, low-fat diet.
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Figure 6: Neither DIO nor MCD deficiency alters the expression of proteins involved in energy metabolism and mitochondrial function. A: PGC1-α expression is not altered by DIO or MCD deficiency. B: UCP2 expression is not altered by DIO or MCD deficiency. Values represent means ± SE (n = 4 per group). ■, MCD−/−; □, WT. HF, high-fat diet; KO, knockout; LF, low-fat diet.

Mentions: Several proteins including PPAR-γ coactivator 1α (PGC1-α) and uncoupling protein 2 (UCP2) have been proposed to be altered by DIO in both skeletal and cardiac muscle (12,21–24). Neither the expression of PGC1-α (Fig. 6A) or UCP2 (Fig. 6B) was altered by DIO in either the WT or MCD−/− groups. Supporting improved cardiac insulin sensitivity in MCD−/− DIO mice, we demonstrate an increase in Akt serine 473 phosphorylation and a trend to an increased glycogen synthase kinase 3β serine 9 phosphorylation in MCD−/− DIO hearts (P = 0.09) perfused aerobically with insulin (Fig. 7A and B). Insulin had no effect on 5′AMP-activated protein kinase (AMPK) phosphorylation at threonine 172 (Fig. 7C), suggesting that AMPK likely does not play a role in the improved insulin sensitivity observed in MCD−/− 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)

Neither DIO nor MCD deficiency alters the expression of proteins involved in energy metabolism and mitochondrial function. A: PGC1-α expression is not altered by DIO or MCD deficiency. B: UCP2 expression is not altered by DIO or MCD deficiency. Values represent means ± SE (n = 4 per group). ■, MCD−/−; □, WT. HF, high-fat diet; KO, knockout; LF, low-fat diet.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 6: Neither DIO nor MCD deficiency alters the expression of proteins involved in energy metabolism and mitochondrial function. A: PGC1-α expression is not altered by DIO or MCD deficiency. B: UCP2 expression is not altered by DIO or MCD deficiency. Values represent means ± SE (n = 4 per group). ■, MCD−/−; □, WT. HF, high-fat diet; KO, knockout; LF, low-fat diet.
Mentions: Several proteins including PPAR-γ coactivator 1α (PGC1-α) and uncoupling protein 2 (UCP2) have been proposed to be altered by DIO in both skeletal and cardiac muscle (12,21–24). Neither the expression of PGC1-α (Fig. 6A) or UCP2 (Fig. 6B) was altered by DIO in either the WT or MCD−/− groups. Supporting improved cardiac insulin sensitivity in MCD−/− DIO mice, we demonstrate an increase in Akt serine 473 phosphorylation and a trend to an increased glycogen synthase kinase 3β serine 9 phosphorylation in MCD−/− DIO hearts (P = 0.09) perfused aerobically with insulin (Fig. 7A and B). Insulin had no effect on 5′AMP-activated protein kinase (AMPK) phosphorylation at threonine 172 (Fig. 7C), suggesting that AMPK likely does not play a role in the improved insulin sensitivity observed in MCD−/− 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