New research from the University of Michigan suggests that harnessing certain proteins in the brain could make popular diabetes and weight-loss drugs more effective and reduce their side effects.
This study, published in the Journal of Clinical Investigation, focused on two proteins, melanocortin 3 (MC3R) and melanocortin 4 (MC4R), which are mainly found on the surface of neurons in the brain and play a key role in controlling eating habits and energy balance.
Melanocortin 3 and melanocortin 4 proteins help the body monitor long-term energy reserves and process signals from the stomach about short-term fullness, or satiety.
“These proteins impact everything from sensing long-term energy stores to processing signals from the gut regarding short-term fullness,” explained Roger Cone, the study’s lead researcher and a physiologist at the University of Michigan.
The study explored how GLP-1 agonists, a class of drugs including semaglutides (e.g., Ozempic) and tirzepatides (e.g., Mounjaro), interact with the melanocortin system. These drugs mimic a natural hormone produced by the gut when it is full, signaling the brain to reduce food intake.
They are effective in treating type 2 diabetes and obesity, and may also help with heart disease and addiction. “We wanted to understand how these GLP-1 drugs function when we enhance the melanocortin system,” said Cone.
Cone and his team conducted experiments on mice to test several hormones that reduce food intake. They compared the results in normal mice with mice that lacked the MC3R protein, mice treated with chemicals to block MC3R, and mice given a drug to boost MC4R activity.
Since MC3R naturally inhibits MC4R, blocking MC3R and increasing MC4R activity have similar effects.
The results were promising. Naima Dahir, the study’s first author, and her colleagues found that manipulating the melanocortin system—either by inhibiting MC3R or boosting MC4R activity—made the mice more sensitive to GLP-1 drugs and other hormones affecting feeding behavior.
Mice treated with both a GLP-1 drug and an MC4R agonist or MC3R antagonist lost up to five times more weight and reduced their food intake more than those receiving only GLP-1 drugs.
“We found that activating the central melanocortin system hypersensitizes animals to the effects of not just GLP-1s, but to every anti-feeding hormone we tested,” said Cone.
Importantly, the researchers observed that this combination did not increase activity in brain areas associated with nausea, a common side effect of GLP-1 drugs. Instead, the combination significantly increased the drugs’ activation of neurons in the brain’s hypothalamic feeding centers, which control hunger.
These findings suggest that pairing GLP-1 drugs with an MC4R agonist could enhance the drugs’ desired effects without increasing side effects.
This approach could allow patients sensitive to side effects to take lower doses or improve outcomes for patients who have not responded well to existing dosages. However, further drug development and clinical testing are needed.
Although this research has been conducted only in mice, Cone is optimistic about its applicability to humans. “The melanocortin system is highly conserved in humans,” he said.
“Everything we’ve observed in mice over the past decades studying these proteins has also been found in humans, so I suspect that these results would also be translatable to patients.”
The study was a collaborative effort involving researchers from the University of Michigan, the University of Illinois, and Courage Therapeutics. In addition to Cone and Dahir, the study’s authors include Yijun Gui, Yanan Wu, Alix Rouault, Savannah Williams, Luis Gimenez, Stephen Joy, Anna K. Mapp, Patrick Sweeney, and Tomi Sawyer.
This research offers a potential new avenue for improving the effectiveness of diabetes and weight-loss drugs, bringing hope to many patients struggling with these conditions.
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The research findings can be found in Journal of Clinical Investigation.
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