Triglycerides induce leptin resistance at the blood-brain barrier
Triglycerides induce leptin resistance at the blood-brain barrier
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DOI：
10.2337/diabetes.53.5.1253
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发表时间：
2004-05-01
期刊：
影响因子：
7.7
通讯作者：
Morley, JE
中科院分区：
文献类型：
--
作者：
Banks, WA;Coon, AB;Morley, JE
肥胖与瘦素抵抗有关，高瘦素血症就是证据。抗性产生于瘦素通过血脑屏障（BBB）的运输受损、瘦素受体信号传导缺陷以及下游神经元回路的阻断。这种抵抗的介质是未知的。在这里，我们通过血脑屏障的体内、体外和原位模型表明，含有98%甘油三酯的牛奶可以立即抑制瘦素的运输。脱脂牛奶和植物甘油三酯的来源脂内脂没有效果。饥饿和饮食引起的肥胖都会升高甘油三酯并减少血脑屏障中瘦素的运输，而短期禁食会降低甘油三酯并增加运输。静脉注射四种甘油三酯中的三种可以抑制血脑屏障中瘦素的运输，但它们的游离脂肪酸成分没有作用。用一种专门降低甘油三酯水平的药物吉非齐尔治疗，逆转了高甘油三酯血症和瘦素运输受损。我们得出结论，甘油三酯是血脑屏障运输受损介导的瘦素抵抗的重要原因，并表明甘油三酯介导的瘦素抵抗可能已经进化为饥饿期间的抗厌食机制。降低甘油三酯可能通过增强瘦素在血脑屏障中的运输来增强瘦素的厌食作用。
Obesity is associated with leptin resistance as evidenced by hyperleptinemia. Resistance arises from impaired leptin transport across the blood-brain barrier (BBB), defects in leptin receptor signaling, and blockades in downstream neuronal circuitries. The mediator of this resistance is unknown. Here, we show that milk, for which fats are 98% triglycerides, immediately inhibited leptin transport as assessed with in vivo, in vitro, and in situ models of the BBB. Fat-free milk and intralipid, a source of vegetable triglycerides, were without effect. Both starvation and diet-induced obesity elevated triglycerides and decreased the transport of leptin across the BBB, whereas short-term fasting decreased triglycerides and increased transport. Three of four triglycerides tested intravenously inhibited transport of leptin across the BBB, but their free fatty acid constituents were without effect. Treatment with gemfibrozil, a drug that specifically reduces triglyceride levels, reversed both hypertriglyceridemia and impaired leptin transport. We conclude that triglycerides are an important cause of leptin resistance as mediated by impaired transport across the BBB and suggest that triglyceride-mediated leptin resistance may have evolved as an anti-anorectic mechanism during starvation. Decreasing triglycerides may potentiate the anorectic effect of leptin by enhancing leptin transport across the BBB.