Scientists Find Hidden Switch Controlling Hunger

Scientists have discovered a hidden mechanism in the brain that helps control hunger.

A small protein called MRAP2 was found to act like a guide, helping a key hunger receptor reach the cell surface where it can send stronger “I’m full” signals.

MC4R: A Key Player in Appetite Regulation

MC4R is a crucial receptor that responds to the peptide hormone MSH and plays a central role in the work of the Collaborative Research Centre 1423, where researchers are studying it in detail both structurally and functionally. Variations in the MC4R gene are known to be among the most common genetic contributors to 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.

MRAP2’s Role in Receptor Function

Through the use of advanced fluorescence microscopy and single-cell imaging, researchers discovered that a protein called MRAP2 plays a key role in shaping how MC4R is positioned and behaves inside cells. Fluorescent biosensors and confocal imaging revealed that MRAP2 is essential for moving MC4R to the surface of cells, allowing it to more effectively send appetite-suppressing signals.

This discovery reveals an additional layer of control in how hunger is regulated and could inspire new therapies that imitate or adjust MRAP2’s activity to treat obesity and related metabolic diseases. Professor Heike Biebermann, project leader at CRC 1423 and co-lead author of the study from the Institute of Experimental Pediatric Endocrinology at Charité, notes that this international and interdisciplinary effort combined multiple experimental methods and perspectives to uncover key physiological and pathophysiological insights into appetite regulation with potential clinical impact.

Innovative Bioimaging Approaches

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.

Reference: “MRAP2 modifies the signaling and oligomerization state of the melanocortin-4 receptor” by Iqra Sohail, Suli-Anne Laurin, Gunnar Kleinau, Vidicha Chunilal, Andrew Morton, Alfonso Brenlla, Zeynep Cansu Uretmen Kagiali, Marie-José Blouin, Javier A. Tello, Annette G. Beck-Sickinger, Martin J. Lohse, Patrick Scheerer, Michel Bouvier, Peter McCormick, Paolo Annibale and Heike Biebermann, 25 September 2025, Nature Communications.
DOI: 10.1038/s41467-025-63988-w

About CRC 1423

CRC 1423 is a four-year research center 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.

Never miss a breakthrough: Join the SciTechDaily newsletter.
Follow us on Google and Google News.