Atkinson Laura L, Fischer Melanie A, Lopaschuk Gary D
Cardiovascular Research Group, Muttart Diabetes Research and Training Center, Department of Pediatrics, Faculty of Medicine, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
J Biol Chem. 2002 Aug 16;277(33):29424-30. doi: 10.1074/jbc.M203813200. Epub 2002 Jun 10.
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-(3)H]palmitate and 5 mm [1-(14)C]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.
瘦素通过将脂肪酸分配至氧化过程而非三酰甘油（TG）储存过程来调节肝脏、骨骼肌和胰腺中的脂肪酸代谢。尽管心脏中存在瘦素受体，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，给离体工作的大鼠心脏灌注0.8 mM [9,10-(3)H]棕榈酸酯和5 mM [1-(14)C]葡萄糖，以测量棕榈酸酯和葡萄糖的氧化速率。在60分钟的灌注期内，瘦素（60 ng/ml）使棕榈酸酯氧化速率比对照心脏显著增加60%（p < 0.05），并使TG含量降低33%（p < 0.05）。相比之下，瘦素处理组和对照组心脏的葡萄糖氧化速率没有差异。尽管瘦素不影响心脏做功，但氧消耗增加了30%（p < 0.05），心脏效率降低了42%（p < 0.05）。AMP激活的蛋白激酶（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，在调节心脏脂肪酸氧化中起主要作用。瘦素也已被证明通过激活AMPK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灌注5分钟和10分钟后，AMPK活性及其磷酸化状态也未受影响。向灌注液中添加胰岛素（100微单位/ml）降低了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激活心脏中的脂肪酸氧化并降低TG含量。我们还表明，瘦素在心脏中的作用独立于AMPK-ACC-丙二酰辅酶A轴的变化。
