Research uncovers key mechanism for appetite and weight control

MC4R is an important receptor activated by the peptide hormone MSH. It plays a major role in Collaborative Research Centre 1423, where it is being characterised both structurally and functionally. Mutations in MC4R are among the most common genetic causes of severe obesity. “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,” says Dr Patrick Scheerer, project leader at CRC 1423 and co-author of the study, from the Institute of Medical Physics and Biophysics at Charité. Setmelanotide, an approved drug, activates this receptor and specifically reduces feelings of hunger. “We are proud that CRC 1423 has now also contributed to understanding receptor transport and availability,” says Professor Annette Beck-Sickinger, spokesperson for CRC 1423 and co-author of the study. A total of five projects within the Collaborative Research Centre were involved in this interdisciplinary research. 

Using modern fluorescence microscopy and single-cell imaging, the team demonstrated that the protein MRAP2 fundamentally alters the localisation and behaviour of the brain receptor MC4R within cells. Fluorescent biosensors and confocal imaging showed that MRAP2 is essential for transporting MC4R to the cell surface, where it can transmit appetite-suppressing signals more effectively. 

By uncovering this new level of regulation, the study points to therapeutic strategies that mimic or modulate MRAP2 and hold the potential to combat obesity and related metabolic disorders. Professor Heike Biebermann, project leader at CRC 1423 and co-lead author of the study from the Institute of Experimental Pediatric Endocrinology at Charité, emphasises that 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.

The study’s second co-lead author, Dr Paolo Annibale, a lecturer in the School of Physics and Astronomy at the University of St Andrews in the UK, says: “This work was an exciting opportunity to apply several microscopy and bioimaging approaches in a physiologically relevant context. In recent years we have refined this approach to meet the requirements of studying molecular processes in cells.”

This research brought together expertise in live-cell fluorescence microscopy, molecular pharmacology and structural biology from institutions in Germany, Canada and the UK, demonstrating the power of interdisciplinary science to uncover new principles of receptor regulation. 

About CRC 1423

CRC 1423 is a four-year research centre funded by the German Research Foundation (DFG), with five participating institutions: Leipzig University, Martin Luther University Halle-Wittenberg, Charité – Universitätsmedizin Berlin, Heinrich Heine University Düsseldorf, and the University Medical Center Mainz. Researchers from these institutions with backgrounds in biochemistry, biomedicine and computational science are collaborating on an interdisciplinary basis to gain a comprehensive understanding of how structural dynamics affect GPCR function. The Collaborative Research Centre comprises a total of 19 sub-projects.