Department of Medicine and The Diabetes Center.
Department of Ophthalmology, and.
JCI Insight. 2023 Jan 24;8(2):e155900. doi: 10.1172/jci.insight.155900.
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.
G 蛋白偶联受体黑素皮质素 4 受体（MC4R）及其相关蛋白黑素皮质素受体相关蛋白 2（MRAP2）对于人类的食物摄入和体重调节至关重要。MC4R 定位于神经元初级纤毛，这是一种基于微管的细胞器，能够感知和传递细胞外信号。在这里，我们证明了 MRAP2 对于 MC4R 神经元的体重调节功能和 MC4R 的纤毛定位至关重要。更普遍地说，我们的研究还表明，GPCR 向初级纤毛的定位可能需要特定的辅助蛋白，而这些蛋白可能不存在于异源细胞培养系统中。我们的研究结果进一步表明，MC4R 向神经元初级纤毛的靶向定位对于长期能量平衡的控制至关重要，并提示 MC4R 纤毛定位的遗传破坏可能经常是肥胖遗传形式的基础。
