New research shows that a protein the body depends on to control appetite and manage energy does not work alone. Instead, it requires assistance from a second protein. This discovery gives scientists fresh insight into how genetic factors can disrupt appetite regulation and contribute to obesity.
In a study published in Science Signaling today (December 16), an international team led by researchers at the University of Birmingham examined how a partner protein known as MRAP2 supports an appetite-related protein called MC3R. MC3R plays a central role in determining whether the body stores energy or uses it.
Building on earlier discoveries in appetite regulation
Earlier research had already established that MRAP2 is essential for the proper function of a related appetite protein (MC4R), which is known to regulate hunger. The new study set out to determine whether MRAP2 performs a similar supporting role for the structurally related protein MC4R.
To investigate this, the researchers conducted experiments using cell models. They found that when MRAP2 was present in equal amounts with MC3R, cellular signaling became stronger and more effective. This suggests that MRAP2 helps MC3R carry out its job of balancing energy intake with energy expenditure. The team also pinpointed specific regions of MRAP2 that are required for it to support signaling by both MC3R and MC4R.
How genetic mutations disrupt appetite signaling
The researchers then examined what happens when MRAP2 carries genetic mutations that have been identified in some people with obesity. In these tests, mutated versions of the supporter protein (MRAP2) failed to enhance MC3R signaling. As a result, the appetite-regulating protein did not function as effectively.
These findings indicate that changes in MRAP2 can interfere with the hormone system that normally maintains energy balance. When this system is impaired, the body may struggle to properly regulate hunger and energy use.
New insights into obesity risk and potential treatments
Dr. Caroline Gorvin, Associate Professor at the University of Birmingham and lead author of the study, said: “The findings give us some important insights into what’s going on in the hormonal system, related to some key functions like energy balance, appetite, and puberty timing.
“The identification of this protein, MRAP2, as a key aide or supporter to these essential appetite-regulating proteins also gives us new clues for people who have a genetic predisposition to obesity, and how MRAP2 mutations are a clear indication of risk.”
By better understanding how MRAP2 assists appetite-related signaling, researchers hope to determine whether future drugs could target this protein. Such treatments might strengthen feelings of fullness, curb overeating, and restore a healthier energy balance, offering new options for weight loss when dietary changes alone are not enough.
Reference: “The accessory protein MRAP2 directly interacts with melanocortin-3 receptor to enhance signaling” by Aqfan Jamaluddin, Rachael A. Wyatt, Joon Lee, Georgina K. C. Dowsett, John A. Tadross, Johannes Broichhagen, Giles S. H. Yeo, Joshua Levitz and Caroline M. Gorvin, 16 December 2025, Science Signaling.
DOI: 10.1126/scisignal.adu4315
The research was conducted by a team from the Department of Metabolism and Systems Science and the Centre of Membrane Proteins and Receptors (COMPARE). COMPARE is a unique cross-University Research Centre between the Universities of Birmingham and Nottingham aimed at investigating the mechanisms of cell communication in physiology and disease to develop innovative therapies for common conditions such as cardiovascular disease, diabetes or cancer. COMPARE is supported by dedicated, state-of-the-art facilities, including the COMPARE Advanced Imaging Facility, which is open to internal and external researchers from both academia and industry.
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