A recent study from the University of Michigan suggests that a group of proteins in the central nervous system could be utilized to improve the effectiveness and minimize the side effects of common diabetes and weight-loss medications.
The research, published in the Journal of Clinical Investigation, focused on two proteins, melanocortin 3 and melanocortin 4, located on brain neurons that play a crucial role in regulating feeding behaviors and maintaining the body’s energy balance.
These proteins influence various functions such as sensing long-term energy reserves and processing signals related to short-term fullness or satiety, stated Roger Cone, a physiologist at U-M who led the study.
GLP-1 agonists, a class of drugs like semaglutides (e.g., Ozempic) and tirzepatides (e.g., Mounjaro), have shown promise in treating type 2 diabetes, obesity, heart disease, and even addiction by mimicking a natural gut hormone that signals fullness to the brain, thus reducing eating behaviors.
“Our question was: What happens when we modulate the melanocortin system in tandem with these satiety-inducing GLP-1 drugs?” said Cone, a professor at U-M Medical School.
In experiments with mice, Cone and his team investigated the impact of various hormones that decrease food intake. They compared outcomes in normal mice, mice lacking the MC3R protein, mice with blocked MC3R activity, and mice with heightened MC4R activity.
The researchers discovered that adjusting the melanocortin system, either by inhibiting MC3R or enhancing MC4R activity, increased the mice’s receptiveness to GLP-1 drugs and other appetite-regulating hormones. Combining a GLP-1 drug with an MC4R agonist or MC3R antagonist resulted in significantly more weight loss and decreased feeding compared to using GLP-1 drugs alone.
“We found that stimulating the central melanocortin system made animals more responsive to not only GLP-1s but to all appetite-suppressing hormones we tested,” Cone noted.
The researchers also observed that altering the melanocortin system did not intensify nausea responses to GLP-1 drugs. Instead, it increased the activation of feeding-related brain centers when combined with these drugs.
The study proposes that combining current GLP-1 drugs with an MC4R agonist could amplify the desired effects up to fivefold without increasing adverse reactions, potentially allowing for lower dosages or enhanced outcomes in non-responsive patients. However, further research and clinical trials are necessary before implementation.
While the study was conducted on mice, Cone is hopeful that the results will be relevant for humans.
“The melanocortin system is similar in humans,” Cone stated. “The observations from our mouse studies have paralleled findings in human studies conducted over the years; thus, I believe these results could also apply to patients.”
The research received funding from the National Institutes of Health and Courage Therapeutics.
