MRC Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
Université de Paris, BFA, UMR 8251, CNRS, Paris, France.
Mol Metab. 2021 Jun;48:101206. doi: 10.1016/j.molmet.2021.101206. Epub 2021 Mar 6.
Over the past 20 years, insights from human and mouse genetics have illuminated the central role of the brain leptin-melanocortin pathway in controlling mammalian food intake, with genetic disruption resulting in extreme obesity, and more subtle polymorphic variations influencing the population distribution of body weight. At the end of 2020, the U.S. Food and Drug Administration (FDA) approved setmelanotide, a melanocortin 4 receptor agonist, for use in individuals with severe obesity due to either pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency.
Herein, we chart the melanocortin pathway's history, explore its pharmacology, genetics, and physiology, and describe how a neuropeptidergic circuit became an important druggable obesity target.
Unravelling the genetics of the subset of severe obesity has revealed the importance of the melanocortin pathway in appetitive control; coupling this with studying the molecular pharmacology of compounds that bind melanocortin receptors has brought a new obesity drug to the market. This process provides a drug discovery template for complex disorders, which for setmelanotide took 25 years to transform from a single gene into an approved drug.
在过去的 20 年中，人类和小鼠遗传学的研究成果揭示了脑内瘦素-黑皮质素途径在控制哺乳动物摄食中的核心作用，该途径的遗传破坏会导致极度肥胖，而更细微的多态性变异则会影响体重在人群中的分布。2020 年底，美国食品和药物管理局（FDA）批准了黑色素 4 受体激动剂 setmelanotide，用于治疗由于 pro-opiomelanocortin（POMC）、前蛋白转化酶枯草溶菌素/激肽释放酶 1（PCSK1）或瘦素受体（LEPR）缺乏引起的重度肥胖症患者。
本文追溯了黑皮质素途径的历史，探讨了其药理学、遗传学和生理学，并描述了一个神经肽回路如何成为一个重要的可药物治疗的肥胖靶点。
对重度肥胖亚组的遗传学进行剖析，揭示了黑皮质素途径在食欲控制中的重要性；将这一点与研究结合黑皮质素受体的化合物的分子药理学相结合，使一种新的肥胖症药物推向市场。这一过程为复杂疾病的药物发现提供了模板，对于 setmelanotide，这个过程耗时 25 年，才从单个基因转化为批准药物。
