Liraglutide, an anti-diabetic drug and agonist of the glucagon-like peptide one receptor (GLP1R), has recently been approved to treat obesity in individuals with or without type 2 diabetes. Despite its extensive metabolic benefits, the mechanism and site of action of liraglutide remain unclear. Here, we demonstrate that liraglutide is shuttled to target cells in the mouse hypothalamus by specialized ependymoglial cells called tanycytes, bypassing the blood-brain barrier. Selectively silencing GLP1R in tanycytes or inhibiting tanycytic transcytosis by botulinum neurotoxin expression not only hampers liraglutide transport into the brain and its activation of target hypothalamic neurons, but also blocks its anti-obesity effects on food intake, body weight and fat mass, and fatty acid oxidation. Collectively, these striking data indicate that the liraglutide-induced activation of hypothalamic neurons and its downstream metabolic effects are mediated by its tanycytic transport into the mediobasal hypothalamus, strengthening the notion of tanycytes as key regulators of metabolic homeostasis.

利拉鲁肽是一种抗糖尿病药物和胰高血糖素样肽一受体 (GLP1R) 激动剂，最近被批准用于治疗患有或不患有 2 型糖尿病的个体的肥胖症。尽管利拉鲁肽具有广泛的代谢益处，但其作用机制和作用部位仍不清楚。在这里，我们证明利拉鲁肽通过称为单胞的特殊室管膜胶质细胞绕过血脑屏障，穿梭至小鼠下丘脑的靶细胞。通过肉毒杆菌神经毒素表达选择性沉默单细胞中的 GLP1R 或抑制单细胞转胞吞作用不仅会阻碍利拉鲁肽转运至大脑及其对下丘脑目标神经元的激活，而且还会阻止其对食物摄入、体重和脂肪量以及脂肪酸的抗肥胖作用氧化。总的来说，