UC Berkeley

The melanocortin 4 Receptor (MC4R) is a central component of the leptin-melanocortin pathway in the hypothalamus. MC4R plays a critical role in the long-term regulation of energy homeostasis and mutations in MC4R are the most common cause of monogenic obesity. However, the precise molecular and cellular mechanisms underlying the maintenance of energy balance within MC4R expressing neurons are unknown. The expression of MC4R in neurons from the Paraventricular Nucleus of the hypothalamus (PVN) has been shown to be both necessary and sufficient to regulate food intake and body weight, and we discovered that MC4R localizes at the primary cilium of those neurons. Primary cilia are unique microtubule-based organelles that protrude from the cell membrane to sense and relay extracellular signals. In Chapter one, we first mapped the expression of MC4R in the brain, to then determine the extent of MC4R localization at the primary cilia in some of the identified regions. We discovered that, in the PVN, MC4R localization at the primary cilium is dynamic and depends on age and physiological status relayed by MC4R ligands levels. Together, these results shed light on the complex regulation of MC4R bioavailability at the primary cilium. In Chapter two, we found that cilia were required specifically on MC4R-expressing neurons for the control of energy homeostasis. Moreover, these cilia were critical for pharmacological activators of MC4R to exert an anorexigenic effect. Using a combination of mouse genetic approaches, we demonstrated that MC4R signals via cilia of PVN neurons to control food intake and body weight. In Chapter three, we demonstrate that the Melanocortin Receptor Associated Protein 2 (MRAP2) is critical for the ciliary localization and weight-regulating function of MC4R. These findings demonstrate that targeting of MC4R to neuronal primary cilia is essential for the control of long-term energy homeostasis and suggests that genetic disruption of MC4R ciliary localization may frequently underlie inherited forms of obesity.