An ischemic insult is accompanied by an acute increase in circulating fatty acid (FA), which can induce adverse changes related to cardiac metabolism/energetics. Although chronic hyperlipidemia contributes to the pathogenesis of obesity/diabetes-related cardiomyopathy, it unclear how these hearts are affected by an acute high FA-load. We hypothesize that adaptation to chronic FA exposure enhances the obese hearts' ability to handle an acute high FA-load. Diet-induced obese (DIO) and age-matched control (CON) mouse hearts were perfused in the presence of low or high FA-load (0.4 and 1.8 mM). Left ventricular (LV) function, FA oxidation rate, myocardial oxygen consumption and mechanical efficiency were assessed, followed by analysis of myocardial oxidative stress, mitochondrial respiration, protein acetylation as well as gene expression. Finally, ischemic tolerance was determined by examining LV functional recovery and infarct size. Under low FA conditions, DIO hearts showed mild LV dysfunction, oxygen wasting, mechanical inefficiency, and reduced mitochondrial OxPhos. High FA-load increased FA oxidation rates in both groups, but this did not alter any of the above parameters in DIO hearts. In contrast, CON hearts showed FA-induced mechanical inefficiency, oxidative stress and reduced OxPhos, as well as enhanced acetylation and activation of PPARα-dependent gene expression. While high FA-load did not alter functional recovery and infarct size in CON hearts, it increased ischemic tolerance in DIO hearts. Thus, this study demonstrates that acute FA-load affects normal and obese hearts differently, and that chronically elevated circulating FA levels render the DIO heart less vulnerable to the disadvantageous effects of an acute FA-load.

中文翻译：

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饮食诱导的肥胖小鼠心脏可以耐受急性高脂肪酸暴露，从而增加缺血耐受性。

缺血性损伤伴有循环脂肪酸（FA）的急剧增加，这可以诱发与心脏代谢/能量相关的不良变化。尽管慢性高脂血症是肥胖/糖尿病相关性心肌病的病因，但尚不清楚这些心脏如何受到急性高FA负荷的影响。我们假设适应慢性FA暴露可增强肥胖心脏应对急性高FA负荷的能力。在存在低或高FA负荷（0.4和1.8 mM）的情况下灌注饮食诱导的肥胖（DIO）和年龄匹配的对照（CON）小鼠心脏。评估左心室（LV）功能，FA氧化率，心肌耗氧量和机械效率，然后分析心肌氧化应激，线粒体呼吸，蛋白质乙酰化以及基因表达。最后，通过检查左室功能恢复和梗死面积来确定缺血耐受性。在低FA条件下，DIO心脏显示轻度LV功能障碍，氧气浪费，机械效率低下和线粒体OxPhos降低。高FA负荷增加了两组的FA氧化率，但这并没有改变DIO心脏中的上述任何参数。相比之下，CON心脏表现出FA诱导的机械效率低下，氧化应激和减少的OxPhos，以及增强的乙酰化作用和PPARα依赖性基因表达的激活。虽然高FA负荷不会改变CON心脏的功能恢复和梗死面积，但会增加DIO心脏的缺血耐受性。因此，这项研究表明，急性FA负荷对正常和肥胖心脏的影响不同，