Leptin activates cardiac fatty acid oxidation independent of changes in the AMP-activated protein kinase-acetyl-CoA carboxylase-malonyl-CoA axis
Leptin activates cardiac fatty acid oxidation independent of changes in the AMP-activated protein kinase-acetyl-CoA carboxylase-malonyl-CoA axis
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DOI：
10.1074/jbc.m203813200
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发表时间：
2002-08-16
影响因子：
4.8
通讯作者：
Lopaschuk, GD
中科院分区：
文献类型：
--
作者：
Atkinson, LL;Fischer, MA;Lopaschuk, GD
瘦素调节肝脏、骨骼肌和胰腺的脂肪酸代谢，将脂肪酸分解为氧化而不是三酰甘油（TG）储存。虽然瘦素受体存在于心脏中，但尚不清楚瘦素是否也调节心脏脂肪酸代谢。为了确定瘦素是否直接调节心脏脂肪酸代谢，我们将离体工作大鼠心脏灌注0.8 mm [9,10- h -3]棕榈酸酯和5 mm [1-C-14]葡萄糖，测量棕榈酸酯和葡萄糖的氧化速率。60 ng/ml瘦素在60 min灌注期间使棕榈酸氧化率比对照组高60% (p < 0.05)，使TG含量降低33% （p < 0.05）。相比之下，在接受瘦素治疗的心脏和对照组之间，葡萄糖氧化率没有差异。虽然瘦素不影响心脏工作，但耗氧量增加了30% (p < 0.05)，心脏效率降低了42% （p < 0.05）。amp活化蛋白激酶（AMPK）通过抑制乙酰辅酶a羧化酶（ACC）和降低丙二酰辅酶a水平，在心脏脂肪酸氧化中发挥重要作用。瘦素也被证明通过激活AMPK来增加骨骼肌中的脂肪酸氧化。然而，我们证明瘦素对AMPK活性、AMPK磷酸化状态、ACC活性或丙二酰辅酶a水平没有显著影响。在瘦素存在的情况下，AMPK的活性和磷酸化状态在灌注5和10分钟后也不受影响。在灌注液中加入胰岛素（100微克/毫升）可降低瘦素增加脂肪酸氧化和降低心脏TG含量的能力。这些数据首次证明瘦素可以激活脂肪酸氧化并降低心脏中甘油三酯的含量。我们还表明，瘦素在心脏中的作用独立于ampk - acc -丙二醇-辅酶a轴的变化。
Leptin regulates fatty acid metabolism in liver, skeletal muscle, and pancreas by partitioning fatty acids into oxidation rather than triacylglycerol (TG) storage. Although leptin receptors are present in the heart, it is not known whether leptin also regulates cardiac fatty acid metabolism. To determine whether leptin directly regulates cardiac fatty acid metabolism, isolated working rat hearts were perfused with 0.8 mm [9,10-H-3]palmitate and 5 mm [1-C-14]glucose to measure palmitate and glucose oxidation rates. Leptin (60 ng/ml) significantly increased palmitate oxidation rates 60% above control hearts (p < 0.05) and decreased TG content by 33% (p < 0.05) over the 60-min perfusion period. In contrast, there was no difference in glucose oxidation rates between leptin-treated and control hearts. Although leptin did not affect cardiac work, oxygen consumption increased by 30% (p < 0.05) and cardiac efficiency was decreased by 42% (p < 0.05). AMP-activated protein kinase (AMPK) plays a major role in the regulation of cardiac fatty acid oxidation by inhibiting acetyl-CoA carboxylase (ACC) and reducing malonyl-CoA levels. Leptin has also been shown to increase fatty acid oxidation in skeletal muscle through the activation of AMPK. However, we demonstrate that leptin had no significant effect on AMPK activity, AMPK phosphorylation state, ACC activity, or malonyl-CoA levels. AMPK activity and its phosphorylation state were also unaffected after 5 and 10 min of perfusion in the presence of leptin. The addition of insulin (100 microunits/ml) to the perfusate reduced the ability of leptin to increase fatty acid oxidation and decrease cardiac TG content. These data demonstrate for the first time that leptin activates fatty acid oxidation and decreases TG content in the heart. We also show that the effects of leptin in the heart are independent of changes in the AMPK-ACC-malonyl-CoA axis.