Obesity in ciliopathies: How neuronal primary cilia control appetite

项目摘要/摘要 我们研究神经元初级纤毛如何调节能量动态平衡以及如何 它们的失调会导致肥胖。初级纤毛是细胞表面的突起，它接收 并转换精选的细胞间信号。在人类中，初级纤毛功能障碍 导致纤毛病，肥胖是其主要表现的多发性疾病。这个 人类严重肥胖最常见的单基因原因是MC4R基因突变，编码 调节能量动态平衡的下丘脑GPCR。 在这个项目的最初资助期，我们已经证明了MC4R 在体内的初级纤毛的定位和功能，以及它的定位和功能是 依赖于MC4R相关蛋白MRAP2。我们还发现，抑制 MC4R神经元初级纤毛中的腺苷环化酶导致肥胖。这些发现 提示下丘脑神经元利用纤毛通过MC4R进行通讯调节 能量平衡。 在这里，我们建立在这些发现和我们拥有的新的遗传和分子工具的基础上 研究纤毛病变如何扰乱睫状体MC4R信号，如何通过配体 调节其对纤毛的定位，以及MC4R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 能量动态平衡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.