Leptin increases hepatic triglyceride export via a vagal mechanism in humans

Recombinant human leptin (metreleptin) reduces hepatic lipid content in patients with lipodystrophy and overweight patients with non-alcoholic fatty liver disease and relative hypoleptinemia independent of its anorexic action. In rodents, leptin signaling in the brain increases very-low-density lipoprotein triglyceride (VLDL-TG) secretion and reduces hepatic lipid content via the vagus nerve. In this randomized, placebo-controlled crossover trial (EudraCT Nr. 2017-003014-22), we tested whether a comparable mechanism regulates hepatic lipid metabolism in humans. A single metreleptin injection stimulated hepatic VLDL-TG secretion (primary outcome) and reduced hepatic lipid content in fasted, lean men (n = 13, age range 20-38 years) but failed to do so in metabolically healthy liver transplant recipients (n = 9, age range 26-62 years) who represent a model for hepatic denervation. In an independent cohort of lean men (n = 10, age range 23-31 years), vagal stimulation by modified sham feeding replicated the effects of metreleptin on VLDL-TG secretion. Therefore, we propose that leptin has anti-steatotic properties that are independent of food intake by stimulating hepatic VLDL-TG export via a brain-vagus-liver axis.

重组人瘦素（美曲普汀，metreleptin）可降低脂肪营养不良患者以及合并相对性低瘦素血症的非酒精性脂肪性肝病超重患者的肝脏脂质含量，且该作用不依赖其厌食效应。既往啮齿类动物研究显示，脑部瘦素信号可通过迷走神经促进极低密度脂蛋白甘油三酯（VLDL-TG）分泌并降低肝脏脂质含量。本项随机安慰剂对照交叉试验（欧盟临床试验登记号EudraCT Nr. 2017-003014-22）旨在验证人类是否存在类似的调控肝脏脂质代谢的机制。研究纳入13名年龄20~38岁的空腹瘦男性受试者，单次注射美曲普汀可刺激其肝脏VLDL-TG分泌（主要终点）并降低肝脏脂质含量；但在9名年龄26~62岁的代谢健康肝移植受者（该群体为肝脏去神经支配模型）中，未观察到上述效应。在另一项独立队列的10名年龄23~31岁的瘦男性受试者中，改良假喂食诱导的迷走神经刺激可重现美曲普汀对VLDL-TG分泌的调控作用。综上，本研究提出：瘦素可通过激活脑-迷走神经-肝脏轴促进肝脏VLDL-TG输出，从而发挥不依赖进食的抗脂肪变性功效。