Researchers from the University of St Andrews have uncovered how a protein named MRAP2 reshapes the function of a brain receptor called MC4R that plays a central role in appetite control and energy balance.
Mutations in MC4R are among the most common genetic causes of severe obesity.
For some people, existing therapeutic appetite suppressants such as Wegovy or Mounjaro are ineffective or unsuitable.
Yet, due to MC4R acting through a distinct neural circuit to regulate appetite and energy expenditure, new MC4R-targeted therapies could complement the remarkable success of these drugs.
Published in Nature Communications, the study demonstrated that MRAP2 profoundly changes the location and behaviour of MC4R within cells using state-of-the-art fluorescence microscopy and single-cell imaging.
Fluorescent biosensors and confocal imaging revealed that MRAP2 is crucial to moving MC4R to the cell surface, where it can more effectively transmit signals that suppress appetite.
Microscopy also provided direct visual evidence that MRAP2 guides how MC4R molecules are organised — a finding confirmed through molecular brightness and fluorescence cross-correlation spectroscopy.
These results connect receptor structure with changes in signalling dynamics, highlighting MRAP2’s ability to fine-tune MC4R activity.
By uncovering this new regulatory layer, the study points toward fresh therapeutic strategies that mimic or modulate MRAP2, with potential for tackling obesity and related metabolic diseases.
Within St Andrews, the study featured a partnership between the schools of Medicine and Physics and Astronomy.
Co-lead author Dr Paolo Annibale, reader in the School of Physics and Astronomy, said: “This work was an exciting opportunity to put to fruition, in a physiologically relevant setting, several of the microscopy and bioimaging approaches we have been honing."
Co-author Dr Javier Tello, from the School of Medicine, said: “This study provided an exciting opportunity to pinpoint a fundamental mechanism underlying how the body knows when it’s full."
"Discoveries such as this are likely to inform the development of new therapeutic strategies to combat the growing obesity epidemic.”