MRAP2 regulates energy homeostasis by promoting primary cilia localization of MC4R

The G protein-coupled receptor melanocortin-4 receptor (MC4R) and its associated protein melanocortin receptor-associated protein 2 (MRAP2) are essential for the regulation of food intake and body weight in humans. MC4R localizes and functions at the neuronal primary cilium, a microtubule-based organelle that senses and relays extracellular signals. Here, we demonstrate that MRAP2 is critical for the weight-regulating function of MC4R neurons and the ciliary localization of MC4R. More generally, our study also reveals that GPCR localization to primary cilia can require specific accessory proteins that may not be present in heterologous cell culture systems. Our findings further demonstrate that targeting of MC4R to neuronal primary cilia is essential for the control of long-term energy homeostasis and suggest that genetic disruption of MC4R ciliary localization may frequently underlie inherited forms of obesity.

Automated summary

The study reveals the importance of MC4R and MRAP2 in regulating food intake and body weight in humans. MRAP2 plays a critical role in the weight-regulating function of MC4R neurons and the ciliary localization of MC4R. Furthermore, the study suggests that specific accessory proteins are required for GPCR localization to primary cilia, which may not be present in heterologous cell culture systems. The findings also imply that disruption of MC4R ciliary localization may frequently be responsible for inherited forms of obesity.