The melanocortin system, an essential regulator of energy homeostasis in the brain, has drawn increasing attention from researchers aiming to understand the underlying causes of obesity. Central to this system are the melanocortin-4 receptor (MC4R) and adenylyl cyclase 3 (ADCY3), both of which are localized in neuronal primary cilia, specialized subcellular structures involved in signal transduction.
Scientific evidence has long linked mutations in MC4R and ADCY3 to severe forms of obesity in both humans and animal models. More recently, these findings have been expanded to demonstrate that dysfunction in the primary cilia themselves also contributes to disrupted signaling within the melanocortin pathway and subsequent metabolic imbalances.
At the crux of this regulatory system, MC4R functions as a critical mediator of neuron responses to melanocortin peptides, influencing hunger and energy expenditure. ADCY3 plays a supporting role by modulating cyclic AMP (cAMP) levels, a secondary messenger essential for relaying MC4R signals inside cells. When the signaling within these neuronal cilia is disturbed—be it due to genetic mutations or structural defects in the cilia—the normal energy balance is tipped, often leading to increased appetite and reduced energy utilization.
Recent research is focused on how precisely these molecular and structural components interact within the primary cilia to affect whole-body energy dynamics. Understanding the crosstalk between MC4R, ADCY3, and ciliary function offers promising therapeutic potential for targeting genetic and acquired forms of obesity. Future work aims to explore these mechanisms further to develop precision medicine strategies for obesity treatment based on patients’ genetic and molecular profiles.
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