Researchers identify key brain receptor mechanism for appetite and weight control

Researchers at Leipzig University and Charité—Universitätsmedizin Berlin have discovered a key mechanism for appetite and weight control, that helps the brain to regulate feelings of hunger. In their study, scientists from Collaborative Research Center (CRC) 1423 determined how a protein called melanocortin 2 receptor accessory protein 2 (MRAP2) influences the function of the brain receptor melanocortin-4 receptor (MC4R), which plays a central role in appetite control and energy balance.

Effects of MRAP2 at the MC4R. Credit: Nature Communications (2025). DOI: 10.1038/s41467-025-63988-w

MC4R is an important receptor activated by the peptide hormone MSH. It is an important focus of the Collaborative Research Center, where it is being characterized 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 (an approved drug, activates this receptor and specifically reduces feelings of hunger), which we were able to decipher in an earlier study, has enabled us to better understand the new functional data," explained Dr Patrick Scheerer, project leader at CRC 1423 and co-author of the study, from the Institute of Medical Physics and Biophysics at Charité.

"We are proud that CRC 1423 has now also contributed to understanding receptor transport and availability," added Professor Annette Beck-Sickinger, spokesperson for CRC 1423 and co-author of the study. A total of five projects within the Collaborative Research Center 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, emphasised 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.

"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," added 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, Scotland.

The findings were reported in the paper, MRAP2 modifies the signaling and oligomerization state of the melanocortin-4 receptor’, published in Nature Communications. To access this paper, please click here