Ussher John R, Koves Timothy R, Jaswal Jagdip S, Zhang Liyan, Ilkayeva Olga, Dyck Jason R B, Muoio Deborah M, Lopaschuk Gary D
Cardiovascular Research Group, University of Alberta, Edmonton, Canada.
Diabetes. 2009 Aug;58(8):1766-75. doi: 10.2337/db09-0011. Epub 2009 May 28.
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.
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).
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).
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.
脂肪酸氧化能力受损被认为会导致细胞内脂质蓄积、胰岛素抵抗和心脏功能障碍，然而脂肪酸氧化速率过高也可能损害葡萄糖代谢及功能。因此，我们研究了饮食诱导肥胖（DIO）对野生型（WT）小鼠以及丙二酰辅酶A脱羧酶缺陷型（MCD(-/-)；一种促进线粒体脂肪酸氧化的酶）小鼠胰岛素敏感性心脏葡萄糖氧化的影响。
给WT和MCD(-/-)小鼠喂食低脂或高脂饮食12周，评估心肌脂质代谢产物蓄积情况。进行平行喂养研究，以评估离体工作心脏（±胰岛素）的心肌功能和能量代谢（每克干重每分钟纳摩尔数）。
与低脂喂养的WT小鼠相比，DIO显著降低了胰岛素刺激的葡萄糖氧化（167±31对734±125；P<0.05）。DIO处理的MCD(-/-)小鼠表现出更强的胰岛素刺激的葡萄糖氧化（554±82对167±31；P<0.05），且不完全脂肪酸氧化较少，与WT小鼠相比，长链酰基肉碱减少证明了这一点。MCD(-/-)小鼠的长链酰基辅酶A与DIO处理的WT小鼠相似，但三酰甘油水平升高（10.92±3.72对3.29±0.62μmol/g湿重；P<0.05）。
DIO不会损害心脏脂肪酸氧化或功能，心肌脂质蓄积与胰岛素敏感性之间存在分离。我们的结果表明，肥胖时MCD缺乏对心脏无害。
