Huang Wan, Metlakunta Anantha, Dedousis Nikolas, Ortmeyer Heidi K, Stefanovic-Racic Maja, O'Doherty Robert M
Department of Medicine, Division of Endocrinology/Metabolism, University of Pittsburgh, Pittsburgh, Pennsylvania 1526, USA.
Endocrinology. 2009 May;150(5):2169-74. doi: 10.1210/en.2008-1271. Epub 2009 Jan 15.
It is well established that leptin increases the sensitivity of carbohydrate metabolism to the effects of insulin. Leptin and insulin also have potent effects on lipid metabolism. However, the effects of leptin on the regulation of liver lipid metabolism by insulin have not been investigated. The current study addressed the effects of leptin on insulin-regulated hepatic very low-density lipoprotein (VLDL) metabolism in vivo in rats. A 90-min hyperinsulinemic/euglycemic clamp (4 mU/kg x min(-1)) reduced plasma VLDL triglyceride (TG) by about 50% (P < 0.001 vs. saline control). Importantly, a leptin infusion (0.2 microg/kg x min(-1)) in combination with insulin reduced plasma VLDL-TG by about 80% (P < 0.001 vs. insulin alone). These effects did not require altered skeletal muscle lipoprotein lipase activity but did include differential effects of insulin and leptin on liver apolipoprotein (apo) B and TG metabolism. Thus, insulin decreased liver and plasma apoB100/B48 levels (approximately 50%, P < 0.01), increased liver TGs (approximately 20%, P < 0.05), and had no effect on fatty acid oxidation. Conversely, leptin decreased liver TGs (approximately 50%, P < 0.01) and increased fatty acid oxidation (approximately 50%, P < 0.01) but had no effects on liver or plasma apoB levels. Importantly, the TG-depleting and prooxidative effects of leptin were maintained in the presence of insulin. We conclude that leptin additively increases the suppressive effects of insulin on hepatic and systemic VLDL metabolism by stimulating depletion of liver TGs and increasing oxidative metabolism. The net effect of the combined actions of insulin and leptin is to decrease the production and TG content of VLDL particles.
众所周知，瘦素可提高碳水化合物代谢对胰岛素作用的敏感性。瘦素和胰岛素对脂质代谢也有显著影响。然而，瘦素对胰岛素调节肝脏脂质代谢的作用尚未得到研究。本研究探讨了瘦素对大鼠体内胰岛素调节的肝脏极低密度脂蛋白（VLDL）代谢的影响。90分钟的高胰岛素-正常血糖钳夹（4 mU/kg x min(-1)）使血浆VLDL甘油三酯（TG）降低约50%（与生理盐水对照组相比，P < 0.001）。重要的是，瘦素输注（0.2 μg/kg x min(-1)）与胰岛素联合使用可使血浆VLDL-TG降低约80%（与单独使用胰岛素相比，P < 0.001）。这些作用并不需要改变骨骼肌脂蛋白脂肪酶的活性，但确实包括胰岛素和瘦素对肝脏载脂蛋白（apo）B和TG代谢的不同影响。因此，胰岛素降低了肝脏和血浆中apoB100/B48水平（约50%，P < 0.01），增加了肝脏TGs（约20%，P < 0.05），并且对脂肪酸氧化没有影响。相反，瘦素降低了肝脏TGs（约50%，P < 0.01）并增加了脂肪酸氧化（约50%，P < 0.01），但对肝脏或血浆apoB水平没有影响。重要的是，在存在胰岛素的情况下，瘦素的TG消耗和促氧化作用得以维持。我们得出结论，瘦素通过刺激肝脏TGs的消耗和增加氧化代谢，累加地增强了胰岛素对肝脏和全身VLDL代谢的抑制作用。胰岛素和瘦素联合作用的净效应是降低VLDL颗粒的产生和TG含量。
