Discovery of a Brain Receptor Mechanism Critical for Appetite and Weight Regulation

Researchers from Leipzig University and Charité—Universitätsmedizin Berlin have made a significant breakthrough in understanding how the brain controls hunger and energy balance. Their study uncovers a crucial mechanism involving the protein MRAP2 (melanocortin 2 receptor accessory protein 2), which influences the function of the melanocortin-4 receptor (MC4R). MC4R is a vital receptor activated by the peptide hormone MSH, playing a central role in regulating appetite and body weight. Mutations in MC4R are among the most common genetic causes of severe obesity.

The research, published in Nature Communications, demonstrates that MRAP2 is essential for transporting MC4R to the cell surface, where it can effectively transmit signals that suppress appetite. Using advanced fluorescence microscopy and single-cell imaging techniques, the team showed that MRAP2 alters the localization and behavior of MC4R within cells, facilitating its movement to the cell membrane. This process enhances the receptor's ability to send signals that reduce feelings of hunger.

These findings have significant implications for obesity treatment. The drug setmelanotide, which activates MC4R, is already approved for reducing hunger and promoting weight loss. By understanding how MRAP2 modulates MC4R's transport and availability, new therapeutic strategies could be developed to mimic or enhance this process, offering promising avenues to combat obesity and related metabolic disorders.

The collaborative effort involved multiple interdisciplinary projects within CRC 1423—Structural Dynamics of GPCR Activation and Signaling—which combined structural and functional analysis of MC4R. This research highlights the importance of the physical interaction between MRAP2 and MC4R in regulating appetite and provides a potential target for future obesity interventions.

The study also underscores the power of combining modern bioimaging approaches with cellular and molecular techniques, enabling a deeper understanding of physiological mechanisms. The international collaboration included experts from Leipzig University, Charité, and the University of St Andrews, whose diverse approaches contributed to these important discoveries about appetite regulation.