The heart alters the rate and relative oxidation of fatty acids and glucose based on availability and energetic demand. Insulin plays a crucial role in this process diminishing fatty acid and increasing glucose oxidation when glucose availability increases. Loss of insulin sensitivity and metabolic flexibility can result in cardiovascular disease. It is therefore important to identify mechanisms by which insulin regulates substrate utilization in the heart. Mitochondrial pyruvate dehydrogenase (PDH) is the key regulatory site for the oxidation of glucose for ATP production. Nevertheless, the impact of insulin on PDH activity has not been fully delineated, particularly in the heart. We sought evidence that insulin stimulates cardiac PDH and that this process is driven by the inhibition of fatty acid oxidation. Mice injected with insulin exhibited dephosphorylation and activation of cardiac PDH. This was accompanied by an increase in the content of malonyl-CoA, an inhibitor of carnitine palmitoyltransferase 1 (CPT1), and, thus, mitochondrial import of fatty acids. Administration of the CPT1 inhibitor oxfenicine was sufficient to activate PDH. Malonyl-CoA is produced by acetyl-CoA carboxylase (ACC). Pharmacologic inhibition or knockout of cardiac ACC diminished insulin-dependent production of malonyl-CoA and activation of PDH. Finally, circulating insulin and cardiac glucose utilization exhibit daily rhythms reflective of nutritional status. We demonstrate that time-of-day-dependent changes in PDH activity are mediated, in part, by ACC-dependent production of malonyl-CoA. Thus, by inhibiting fatty acid oxidation, insulin reciprocally activates PDH. These studies identify potential molecular targets to promote cardiac glucose oxidation and treat heart disease.

中文翻译：

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胰岛素对心脏β-氧化和丙酮酸脱氢酶的相互调节


心脏根据可用性和能量需求改变脂肪酸和葡萄糖的速率和相对氧化。当葡萄糖利用率增加时，胰岛素在减少脂肪酸和增加葡萄糖氧化的过程中起着至关重要的作用。胰岛素敏感性和代谢灵活性丧失可能导致心血管疾病。因此，确定胰岛素调节心脏底物利用的机制非常重要。线粒体丙酮酸脱氢酶 (PDH) 是葡萄糖氧化产生 ATP 的关键调节位点。然而，胰岛素对 PDH 活性的影响尚未完全阐明，特别是在心脏中。我们寻找证据证明胰岛素刺激心脏 PDH，并且该过程是由抑制脂肪酸氧化驱动的。注射胰岛素的小鼠表现出心脏 PDH 的去磷酸化和激活。与此同时，肉毒碱棕榈酰转移酶 1 (CPT1) 抑制剂丙二酰辅酶 A 的含量增加，从而导致线粒体输入脂肪酸。施用 CPT1 抑制剂奥芬尼辛足以激活 PDH。丙二酰辅酶 A 由乙酰辅酶 A 羧化酶 (ACC) 产生。药物抑制或敲除心脏 ACC 会减少胰岛素依赖性丙二酰辅酶 A 的产生和 PDH 的激活。最后，循环胰岛素和心脏葡萄糖利用表现出反映营养状况的每日节律。我们证明，PDH 活性随时间的变化部分是由 ACC 依赖性丙二酰辅酶 A 的产生介导的。因此，通过抑制脂肪酸氧化，胰岛素反过来激活PDH。这些研究确定了促进心脏葡萄糖氧化和治疗心脏病的潜在分子靶点。