Scientists discover protein that switches off hunger
Researchers have identified how a protein called MRAP2 regulates hunger by transporting the brain receptor MC4R to the cell surface, enhancing appetite-suppressing signals. This finding, from a study involving institutions in Germany, Canada, and the UK, could lead to new obesity treatments. The work was published in Nature Communications.
A team of scientists from Leipzig University and Charité – Universitätsmedizin Berlin, part of the Collaborative Research Centre (CRC) 1423, has uncovered a key mechanism in appetite control. The protein MRAP2 (melanocortin 2 receptor accessory protein 2) influences the melanocortin-4 receptor (MC4R), which is activated by the peptide hormone MSH and plays a central role in energy balance. Mutations in MC4R are among the most common genetic causes of severe obesity.
Using modern fluorescence microscopy and single-cell imaging, the researchers demonstrated that MRAP2 is essential for moving MC4R to the cell surface, where it can transmit stronger "stop eating" signals. This alters the receptor's localisation and behavior within cells, as shown through fluorescent biosensors and confocal imaging.
Dr. Patrick Scheerer, project leader at CRC 1423 from the Institute of Medical Physics and Biophysics at Charité, noted: "The knowledge of the 3D structures of the active receptor in interaction with ligands and drugs such as setmelanotide, which we were able to decipher in an earlier study, has enabled us to better understand the new functional data." Setmelanotide is an approved drug that activates MC4R to reduce hunger.
Professor Annette Beck-Sickinger, spokesperson for CRC 1423, added: "We are proud that CRC 1423 has now also contributed to understanding receptor transport and availability." The study involved five projects within the centre and drew on expertise in live-cell fluorescence microscopy, molecular pharmacology, and structural biology from Germany, Canada, and the UK.
Professor Heike Biebermann, from the Institute of Experimental Pediatric Endocrinology at Charité, emphasized the interdisciplinary approach: "This interdisciplinary and international collaboration enabled researchers, using different approaches and diverse experimental methods, to uncover important new physiological and pathophysiological aspects of appetite regulation with therapeutic relevance."
Dr. Paolo Annibale from the University of St Andrews said: "This work was an exciting opportunity to apply several microscopy and bioimaging approaches in a physiologically relevant context."
The discovery suggests potential therapeutic strategies to mimic or modulate MRAP2 for combating obesity and metabolic disorders. CRC 1423, funded by the German Research Foundation, involves 19 sub-projects across five institutions focused on GPCR function.