Obesity in ciliopathies: How neuronal primary cilia control appetite

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.