Recent findings from the University of Michigan suggest that a network of proteins within the central nervous system could enhance the efficacy and mitigate side effects of common diabetes and weight-loss medications. They were published today in the Journal of Clinical Investigation; the research centres on two proteins, melanocortin three and melanocortin 4, located predominantly on the surface of brain neurons. These proteins are crucial in regulating feeding behaviours and maintaining energy balance in the body.
Roger Cone, a U-M physiologist who spearheaded the research, explained that melanocortin three and melanocortin 4 influence a range of functions, from monitoring long-term energy reserves to interpreting signals from the gut about short-term fullness or satiety. The study mainly looks at GLP-1 agonists—such as semaglutides and tirzepatides—renowned for their effectiveness against not only type 2 diabetes but also obesity, heart disease, and potentially addiction. These drugs operate by emulating a natural hormone produced by the gut when complete, which then prompts the brain to curb feeding behaviour.
Cone posed a critical question: “How do GLP-1 drugs, which modulate satiety signals, perform when we prime the melanocortin system?” To explore this, his team conducted experiments using mouse models, comparing the effects of various hormones that decrease food intake. They tested these hormones in typical mice, in those lacking the MC3R protein genetically, in mice treated with chemicals that inhibit MC3R, and in those administered a drug that enhances MC4R activity. Since MC3R naturally curtails MC4R activity, blocking MC3R while boosting MC4R has comparable outcomes.
The study, led by first author Naima Dahir, a postdoctoral research fellow in Cone’s lab, discovered that either inhibiting MC3R or boosting MC4R activity heightened the mice’s sensitivity to GLP-1 drugs and other hormones impacting feeding behaviour. Mice treated with a combination of a GLP-1 drug and either an MC4R agonist or an MC3R antagonist experienced up to a fivefold increase in weight loss and reduced feeding compared to those treated solely with GLP-1 drugs.
“Our findings reveal that activating the central melanocortin system significantly increases the response to not just GLP-1s, but to all anti-feeding hormones we tested,” noted Cone. The research team also monitored brain activity associated with nausea—a common side effect of GLP-1 drugs—and found no increase in such activity when GLP-1 drugs were used alongside modifications to the melanocortin system. In contrast, we stimulated melanocortin neurons, which markedly enhanced the GLP-1 drug-induced activation of neurons in brain areas responsible for feeding.
These results suggest that combining existing GLP-1 drugs with an MC4R agonist could amplify the drugs’ desired effects fivefold without exacerbating unwanted side effects. This approach could allow patients who are particularly sensitive to side effects to use lower doses or enhance outcomes for patients who are unresponsive to current drug dosages. However, further drug development and clinical trials are necessary before such treatments can be implemented.
Although the research was conducted in mouse models, Cone remains optimistic about its applicability to humans. “The melanocortin system is highly conserved in humans,” he remarked. “Based on our decades of research into these proteins, which has shown consistent results between mice and humans, I believe these findings will likely be transferable to clinical settings.”
More information: Naima S. Dahir et al, Subthreshold activation of the melanocortin system causes generalized sensitization to anorectic agents in mice, Journal of Clinical Investigation. DOI: 10.1172/JCI178250
Journal information: Journal of Clinical Investigation Provided by University of Michigan
