Metabolic health depends on the brain’s ability to control food intake and nutrient use versus storage, processes that require peripheral signals such as the adipocyte-derived hormone, leptin, to cross brain barriers and mobilize regulatory circuits. We have previously shown that hypothalamic tanycytes shuttle leptin into the brain to reach target neurons. Here, using multiple complementary models, we show that tanycytes express functional leptin receptor (LepR), respond to leptin by triggering Ca²⁺ waves and target protein phosphorylation, and that their transcytotic transport of leptin requires the activation of a LepR–EGFR complex by leptin and EGF sequentially. Selective deletion of LepR in tanycytes blocks leptin entry into the brain, inducing not only increased food intake and lipogenesis but also glucose intolerance through attenuated insulin secretion by pancreatic β-cells, possibly via altered sympathetic nervous tone. Tanycytic LepRb–EGFR-mediated transport of leptin could thus be crucial to the pathophysiology of diabetes in addition to obesity, with therapeutic implications.

代谢健康取决于大脑控制食物摄入和营养使用与储存的能力，这些过程需要诸如脂肪细胞衍生激素瘦素等外围信号来跨越大脑屏障并调动调节回路。我们之前已经表明，下丘脑单核细胞将瘦素穿梭到大脑中以到达目标神经元。在这里，我们使用多个互补模型，表明单核细胞表达功能性瘦素受体 (LepR)，通过触发 Ca ^{2+对瘦素作出反应}波和靶蛋白磷酸化，并且它们的瘦素跨细胞转运需要瘦素和EGF依次激活LepR-EGFR复合物。单核细胞中 LepR 的选择性缺失会阻止瘦素进入大脑，不仅会导致食物摄入和脂肪生成增加，还会通过胰腺 β 细胞分泌的胰岛素减弱（可能通过改变交感神经张力）导致葡萄糖不耐受。因此，除肥胖症外，Tanycytic LepRb-EGFR 介导的瘦素转运对糖尿病的病理生理学至关重要，具有治疗意义。