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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 PDH activity in DIO mice despite an increased expression of PDK4. A: MCD−/− DIO mice had an increased expression of the PPAR target gene PDK4. B: The active portion of the PDH complex was higher in MCD−/− DIO mice. C: Total PDH activity was also higher in MCD−/− DIO mice. D: However, the percentage of active PDH did not differ between MCD−/− DIO and WT DIO mice. Values represent means ± SE (n = 6). Differences were determined using a Student's two-tailed t test. *P < 0.05, significantly different from WT DIO mice.
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Figure 2: MCD deficiency improves PDH activity in DIO mice despite an increased expression of PDK4. A: MCD−/− DIO mice had an increased expression of the PPAR target gene PDK4. B: The active portion of the PDH complex was higher in MCD−/− DIO mice. C: Total PDH activity was also higher in MCD−/− DIO mice. D: However, the percentage of active PDH did not differ between MCD−/− DIO and WT DIO mice. Values represent means ± SE (n = 6). Differences were determined using a Student's two-tailed t test. *P < 0.05, significantly different from WT DIO mice.

Mentions: Insulin stimulation of glucose oxidation was significantly increased in MCD−/− mice compared with WT mice in both the low fat–fed and DIO groups (Fig. 1A). This was accompanied by a significant decrease in fatty acid oxidation in low fat–fed MCD−/− mice and a small nonsignificant decrease in fatty acid oxidation in MCD−/− DIO mice, which may be attributed to a trend toward lower fatty acid oxidation rates in the absence of insulin (Fig. 1B). As such, the contribution of glucose oxidation for acetyl CoA production was significantly increased whereas the contribution of fatty acid oxidation for acetyl CoA production was significantly decreased in MCD−/− DIO mice, illustrating that these mice rely less on fatty acids for energy metabolism versus their WT counterparts (Fig. 1C). Paralleling our earlier work in MCD−/− mice whereby compensatory increases in PPAR-α target gene mRNA expression could explain the lack of change in myocardial fatty acid oxidation rates in MCD−/− mice, we show that MCD−/− DIO hearts had higher PPAR-α target gene pyruvate dehydrogenase kinase (PDK)-4 protein expression (Fig. 2A). Despite this elevation in PDK4 expression, total PDH activity and the active state of PDH were significantly higher in hearts from MCD−/− DIO mice, but the ratio of active to total PDH activity remained the same in both groups (Fig. 2B and D). Nonetheless, these findings demonstrate that decreasing MCD can partially overcome the dramatic impairment in insulin-stimulated glucose metabolism seen with DIO, which may be due to a preservation of PDH activity.


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 PDH activity in DIO mice despite an increased expression of PDK4. A: MCD−/− DIO mice had an increased expression of the PPAR target gene PDK4. B: The active portion of the PDH complex was higher in MCD−/− DIO mice. C: Total PDH activity was also higher in MCD−/− DIO mice. D: However, the percentage of active PDH did not differ between MCD−/− DIO and WT DIO mice. Values represent means ± SE (n = 6). Differences were determined using a Student's two-tailed t test. *P < 0.05, significantly different from WT DIO mice.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 2: MCD deficiency improves PDH activity in DIO mice despite an increased expression of PDK4. A: MCD−/− DIO mice had an increased expression of the PPAR target gene PDK4. B: The active portion of the PDH complex was higher in MCD−/− DIO mice. C: Total PDH activity was also higher in MCD−/− DIO mice. D: However, the percentage of active PDH did not differ between MCD−/− DIO and WT DIO mice. Values represent means ± SE (n = 6). Differences were determined using a Student's two-tailed t test. *P < 0.05, significantly different from WT DIO mice.
Mentions: Insulin stimulation of glucose oxidation was significantly increased in MCD−/− mice compared with WT mice in both the low fat–fed and DIO groups (Fig. 1A). This was accompanied by a significant decrease in fatty acid oxidation in low fat–fed MCD−/− mice and a small nonsignificant decrease in fatty acid oxidation in MCD−/− DIO mice, which may be attributed to a trend toward lower fatty acid oxidation rates in the absence of insulin (Fig. 1B). As such, the contribution of glucose oxidation for acetyl CoA production was significantly increased whereas the contribution of fatty acid oxidation for acetyl CoA production was significantly decreased in MCD−/− DIO mice, illustrating that these mice rely less on fatty acids for energy metabolism versus their WT counterparts (Fig. 1C). Paralleling our earlier work in MCD−/− mice whereby compensatory increases in PPAR-α target gene mRNA expression could explain the lack of change in myocardial fatty acid oxidation rates in MCD−/− mice, we show that MCD−/− DIO hearts had higher PPAR-α target gene pyruvate dehydrogenase kinase (PDK)-4 protein expression (Fig. 2A). Despite this elevation in PDK4 expression, total PDH activity and the active state of PDH were significantly higher in hearts from MCD−/− DIO mice, but the ratio of active to total PDH activity remained the same in both groups (Fig. 2B and D). Nonetheless, these findings demonstrate that decreasing MCD can partially overcome the dramatic impairment in insulin-stimulated glucose metabolism seen with DIO, which may be due to a preservation of PDH activity.

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