Adropin regulates cardiac energy metabolism and improves cardiac function and efficiency
Adropin regulates cardiac energy metabolism and improves cardiac function and efficiency
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DOI：
10.1016/j.metabol.2019.06.005
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发表时间：
2019-09-01
影响因子：
9.8
通讯作者：
Lopaschuk, Gary D.
中科院分区：
文献类型：
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作者：
Altamimi, Tariq R.;Gao, Su;Lopaschuk, Gary D.
背景：胰岛素信号转导受损和高脂肪酸氧化率是胰岛素抵抗和糖尿病心肌病的特征。尽管阿德罗平在骨骼肌中可以优先促进糖代谢和改善胰岛素敏感性，但阿德罗平等肝源性多肽在介导这些心脏能量代谢变化中的潜在作用尚不清楚。目的：确定阿德罗平对心脏能量代谢、胰岛素信号转导和心脏效率的影响。方法：C57BL/6小鼠注射载体或分泌型阿德罗平(450nmol/kg，ip)。在24小时内三次。在分离小鼠的心脏并使用工作的心脏系统进行灌流之前，这些小鼠被禁食以强调动物之间阿托品血浆水平的差异。此外，在非禁食小鼠的体外心脏灌流液中直接加入阿德罗平，研究了阿德罗平对心脏代谢和体外功能的急性影响。结果：与观察到的禁食诱导的脂肪酸氧化作为ATP产生来源的优势相反，阿德罗平处理保留了胰岛素对脂肪酸氧化的抑制作用。阿罗平处理的小鼠心脏也显示出更高的心脏做功，与对照心脏相比，伴随着心脏效率的提高和胰岛素信号的增强。有趣的是，与赋形剂处理的心脏相比，急性给药也能抑制脂肪酸氧化，同时强烈刺激葡萄糖氧化。阿罗平也增加了下游心脏胰岛素信号的激活。此外，体内和体外治疗方案均导致葡萄糖氧化的主要酶-丙酮酸脱氢酶(PDH)的抑制性磷酸化、负责蛋白激酶PDH-4的蛋白水平以及JNK(pT183/Y185)和IRS-1(p-S307)的胰岛素信号抑制磷酸化水平降低，提示急性受体和/或翻译后修饰介导的机制。结论：阿曲平对心脏能量代谢有重要影响，可能是治疗与胰岛素敏感性受损相关的心脏病的候选药物。(C)2019 Elsevier Inc.保留所有权利。
Background: Impaired cardiac insulin signalling and high cardiac fatty acid oxidation rates are characteristics of conditions of insulin resistance and diabetic cardiomyopathies. The potential role of liver-derived peptides such as adropin in mediating these changes in cardiac energy metabolismis unclear, despite the fact that in skeletal muscle adropin can preferentially promote glucose metabolism and improve insulin sensitivity.Objectives: To determine the influence of adropin on cardiac energy metabolism, insulin signalling and cardiac efficiency.Methods: C57Bl/6 mice were injected with either vehicle or a secretable form of adropin (450 nmol/kg, i.p.) three times over a 24-h period. The mice were fasted to accentuate the differences between animals in adropin plasma levels before their hearts were isolated and perfused using a working heart system. In addition, direct addition of adropin to the perfusate of ex vivo hearts isolated from non-fasting mice was utilized to investigate the acute effects of the peptide on heart metabolism and ex vivo function.Results: In contrast to the observed fasting-induced predominance of fatty acid oxidation as a source of ATP production in control hearts, insulin inhibition of fatty acid oxidation was preserved by adropin treatment. Adropin-treated mouse hearts also showed a higher cardiac work, whichwas accompanied by improved cardiac efficiency and enhanced insulin signalling compared to control hearts. Interestingly, acute adropin administration to isolated working hearts also resulted in an inhibition of fatty acid oxidation, accompanied by a robust stimulation of glucose oxidation compared to vehicle-treated hearts. Adropin also increased activation of downstream cardiac insulin signalling. Moreover, both in vivo and ex vivo treatment protocols induced a reduction in the inhibitory phosphorylation of pyruvate dehydrogenase (PDH), the major enzyme of glucose oxidation, and the protein levels of the responsible kinase PDH kinase 4 and the insulin-signalling inhibitory phosphorylation of JNK (pT183/Y185) and IRS-1(p-S307), suggesting acute receptor- and/or post-translational modification-mediated mechanisms.Conclusions: These results demonstrate that adropin has important effects on energy metabolism in the heart and may be a putative candidate for the treatment of cardiac disease associated with impaired insulin sensitivity. (C) 2019 Elsevier Inc. All rights reserved.