A protein network found in the central nervous system could be harnessed to boost the effectiveness and reduce the side effects of popular diabetes and weight loss drugs, according to new research from the University of Michigan.
The study, which appears today in the journal Journal of clinical researchfocused on two proteins called melanocortin 3 and melanocortin 4, which are found primarily on the surface of neurons in the brain and play a central role in regulating feeding behavior and maintaining the body’s energy balance.
Melanocortin 3 and melanocortin 4 affect everything from sensing long-term energy stores to the gut’s processing of signals about short-term satiety, said UM physiologist Roger Cone, who led the study.
The class of drugs known as GLP-1 agonists, which includes semaglutides (e.g., Ozempic) and tirzepatides (e.g., Mounjaro), has received a lot of attention recently for its effectiveness in treating not only type 2 diabetes but also obesity, heart disease, and potentially addiction. They work by mimicking a natural hormone that the gut produces when it is full, which causes the brain to reduce eating behavior.
“So the obvious question for us was: How do these GLP-1 drugs, which act by manipulating satiety signals, work when we activate the melanocortin system?” said Cone, a professor of molecular and integrative physiology at the U-M School of Medicine and director of the U-M Life Sciences Institute, where his lab is located.
Cone and his colleagues worked with mouse models to test the effects of various hormones that reduce food intake. They compared the results in normal mice with mice that genetically lacked the MC3R protein, in mice that were given chemicals to block MC3R activity, and in mice that were given a drug to increase MC4R activity. (Since MC3R is a natural negative regulator of MC4R, meaning it decreases MC4R activity, blocking MC3R and increasing MC4R activity have similar effects.)
In all cases, Naima Dahir, first author on the study and a postdoctoral researcher in Cone’s lab, and her colleagues found that adjusting the melanocortin system (either by inhibiting MC3R or increasing MC4R activity) made mice more sensitive to GLP-1 drugs and other hormones that affect feeding behavior. Mice given a GLP-1 drug in combination with either an MC4R agonist or an MC3R antagonist showed up to five times more weight loss and reduced eating than mice given the GLP-1 drugs alone.
“We found that activation of the central melanocortin system hypersensitizes animals not only to the effects of GLP-1, but to all of the antifeedant hormones we tested,” Cone said.
The researchers also measured activity in parts of the brain thought to trigger nausea in response to GLP-1 drugs and did not observe increased activation when the GLP-1 drugs were combined with disruptions to the melanocortin system. In contrast, priming the melanocortin neurons significantly increased GLP-1 drug activation of neurons in the brain’s hypothalamic feeding centers.
The results indicate that combining existing GLP-1 drugs with an MC4R agonist could increase sensitivity to the drugs’ desired effects by up to five-fold, without increasing unwanted side effects. Ultimately, this approach could allow patients who are sensitive to side effects to take a lower dose, or could improve outcomes in patients who have not responded to existing drug doses. Further drug development and clinical testing are needed before this can occur.
Although this research has only been carried out in mouse models, Cone is optimistic that the results will translate well to humans.
“The melanocortin system is highly conserved in humans,” he said. “Everything we’ve seen in mice over the past few decades studying these proteins has also been found in humans, so I suspect these results could be translated to patients as well.”
This research was funded by the National Institutes of Health and Courage Therapeutics.