Obesity in Ciliopathies: How Neuronal Primary Cilia Control Appetite

 描述（由申请人提供）：我们的研究解决了神经元初级纤毛如何控制肥胖。初级纤毛是细胞表面突起，其接收和转导选择的细胞外信号。在人类中，破坏初级纤毛功能的突变会导致 纤毛病，即以肥胖为主要表现的多效性疾病。睫状体功能障碍如何导致肥胖尚不清楚，但被认为涉及神经元信号的破坏 调节能量平衡的途径黑皮质素-4受体（MC 4 R）是调节长期能量稳态的中心介质，并且MC 4 R中的突变是严重人类肥胖的最常见单基因原因。我们已经发现MC 4 R和最近描述的MC 4 R相关蛋白MRAP 2定位于初级纤毛，并且初级纤毛的破坏废除了小鼠中MC 4 R的促凋亡功能。这些结果提示三个重要假设：1）MC 4 R在纤毛中起作用。 2)内源性MC 4 R配体αMSH和AGRP由表达MC 4 R的二级神经元通过其初级纤毛感知，使得这种调节神经元活动的非突触机制成为长期能量稳态的重要组成部分。 3)MC 4 R信号传导的破坏是纤毛疾病中肥胖的原因。我们将通过确定MC 4 R和MRAP 2如何靶向纤毛，纤毛病相关蛋白如何参与MC 4 R功能以及这些蛋白如何通过纤毛发出信号来指示饱腹感来测试这些假设。这项工作将定义神经元调节能量稳态的分子和细胞步骤，并回答长期存在的问题，即纤毛功能障碍如何导致人类肥胖。

 DESCRIPTION (provided by applicant): Our studies address how neuronal primary cilia control obesity. The primary cilium is a cell surface projection that receives and transduces select extracellular signals. In humans, mutations that disrupt the function of primary cilia cause ciliopathies, pleiotropic diseases of which obesity is a cardinal manifestation. How ciliary dysfunction leads to obesity is unclear, but is thought to involve disruption of neuronal signaling pathways that regulate energy homeostasis. The Melanocortin-4 receptor (MC4R) is a central mediator of the regulation of long-term energy homeostasis and mutations in MC4R are the most common monogenic cause of severe human obesity. We have found that MC4R and the recently described MC4R associated protein MRAP2 localize to the primary cilia and that disruption of primary cilia abolishes the anorexigenic function of MC4R in mice. These results suggest three important hypotheses: 1) MC4R functions at the cilium. 2) The endogenous MC4R ligands, αMSH and AGRP, are sensed by the second order MC4R-expressing neurons through their primary cilia, making this non- synaptic mechanism of modulating neuronal activity an important component of long-term energy homeostasis. 3) Disruption of MC4R signaling is the cause of obesity in ciliopathies. We will test these hypotheses by identifying how MC4R and MRAP2 are targeted to cilia, how ciliopathy-associated proteins participate in MC4R function, and how these proteins signal through cilia to indicate satiety. This work will define molecular and cellular steps of neuronal regulation of energy homeostasis and answer the long-standing question of how ciliary dysfunction causes obesity in humans.