Obesity in ciliopathies: How neuronal primary cilia control appetite

项目总结/摘要 我们研究了神经元初级纤毛如何调节能量稳态， 它们的失调导致肥胖。初级纤毛是细胞表面的突起， 和选择性细胞间信号。在人类中，初级纤毛功能的破坏 引起纤毛病变，这是一种多效性疾病，肥胖是其主要表现。的 人类严重肥胖症最常见的单基因原因是MC 4 R突变， 一种调节能量平衡的下丘脑GPCR 在该项目的初始资助期间，我们已经证明MC 4 R 在体内的初级纤毛中定位和起作用，并且其定位和功能是 依赖于MC 4 R相关蛋白MRAP 2。我们还发现， MC 4 R神经元的初级纤毛中的腺苷酸环化酶引起肥胖。这些发现 表明下丘脑神经元通过纤毛与MC 4 R进行通讯， 能量平衡 在这里，我们建立在这些发现的基础上，以及我们拥有的新的遗传和分子工具上， 开发，调查如何纤毛病变破坏睫状MC 4 R信号，如何配体 MC 4 R调节其纤毛定位，以及MC 4 R活性是如何通过 纤毛总之，这些实验将阐明纤毛信号如何编码长期的 能量稳态和神经元如何使用纤毛进行非突触交流。

Project Summary/Abstract We investigate how neuronal primary cilia regulate energy homeostasis and how their dysregulation causes obesity. Primary cilia are cell surface projections that receive and transduce select intercellular signals. In humans, disruption of primary cilia function causes ciliopathies, pleiotropic diseases of which obesity is a cardinal manifestation. The most common monogenic cause of severe human obesity is mutation of MC4R, encoding a hypothalamic GPCR that regulates energy homeostasis. In the initial funding period of this project, we have demonstrated that MC4R localizes and functions at the primary cilia in vivo, and that its localization and function are dependent on the MC4R-associated protein MRAP2. We also found that inhibiting adenylyl cyclase in the primary cilia of MC4R neurons causes obesity. These findings suggest that hypothalamic neurons use cilia to communicate through MC4R to regulate energy homeostasis. Here, we build on these findings, and on new genetic and molecular tools we have developed, to investigate how ciliopathies disrupt ciliary MC4R signaling, how the ligands of MC4R regulate its localization to cilia, and how MC4R activity is transduced by the cilium. Together, these experiments will illuminate how cilia signaling encodes long-term energy homeostasis and how neurons use cilia to communicate non-synaptically.