Nutritionist calculating body mass index of a woman for obesity treatment in a clinic room. Both are women with dark hair and light skin and are sitting opposite each other next to a computer on a table.
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Using drugs to “prime” the melanocortin system could improve the effectiveness, without increasing side effects, of popular diabetes and weight-loss medications, according to new research from the University of Michigan. In one study, mice given a GLP-1 drug in combination with an MC4R agonist or MC3R antagonist showed up to five times more weight loss and reduced feeding than mice receiving only the weight loss 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 U-M physiologist Roger Cone, PhD, who led the research.

The study appeared this week in the Journal of Clinical Investigation. Naima Dahir, a postdoctoral research fellow in Cone’s lab, was the lead author.

Melanocortin 3 and melanocortin 4 are expressed 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. They impact everything from sensing long-term energy stores to processing signals from the gut regarding short-term fullness, or satiety.

The GLP-1 agonists, which include semaglutides (e.g., Ozempic) and tirzepatides (e.g., Mounjaro), have been successful against type 2 diabetes, obesity, heart disease, and potentially addiction. They work by mimicking a natural hormone that the gut produces when it is full, triggering the brain to reduce feeding behavior.

“So the obvious question for us was: How do these GLP-1 drugs, which work by manipulating satiety signals, function when we prime the melanocortin system?” said Cone.

In mouse models, Cone and his colleagues tested the effects of several 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 the activity of MC3R, and in mice that were given a drug to increase the activity of MC4R. (MC3R is a natural negative regulator of MC4R.)

In all cases, they found that adjusting the melanocortin system—either by inhibiting MC3R or increasing MC4R activity—made the mice more sensitive to GLP-1 drugs and other hormones that affect feeding behavior. Mice given a GLP-1 drug in combination with an MC4R agonist or MC3R antagonist showed up to five times more weight loss and reduced feeding than mice receiving only the GLP-1 drugs.

The researchers also measured activity in parts of the brain thought to trigger nausea in response to GLP-1 drugs and observed no increased activation when GLP-1 drugs were combined with alterations to the melanocortin system. In contrast, priming of the melanocortin neurons significantly increased GLP-1 drug activation of neurons in hypothalamic feeding centers in the brain.

Ultimately, this approach could improve the weight loss drugs’ effectiveness and allow patients who are sensitive to the side effects to take a lower dose.

Will this team’s results replicate in people? “The melanocortin system is highly conserved in humans,” Cone said. “Everything we’ve observed in the mouse 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.”

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