New research demonstrates potential for increasing effectiveness of popular diabetes, weight-loss drugs

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Date:
July 15, 2024
Source:
University of Michigan
Summary:
A network of proteins found in the central nervous system could be harnessed to increase the effectiveness and reduce the side effects of popular diabetes and weight-loss drugs, according to new research.

New research from the University of Michigan suggests that a network of proteins found in the central nervous system could be leveraged to enhance the effectiveness and mitigate the side effects of commonly used diabetes and weight-loss medications.

Published in the Journal of Clinical Investigation, the study focused on two proteins known as melanocortin 3 and melanocortin 4, predominantly located on the surface of neurons in the brain. These proteins are pivotal in regulating feeding behavior and maintaining the body's energy balance.


According to U-M physiologist Roger Cone, who led the study, melanocortin 3 and melanocortin 4 influence various aspects, from sensing long-term energy stores to processing signals of short-term fullness (satiety).

The study particularly investigated GLP-1 agonists, such as semaglutides (e.g., Ozempic) and tirzepatides (e.g., Mounjaro), which have gained attention for their effectiveness not only in treating type 2 diabetes but also obesity, heart disease, and potentially addiction. These drugs mimic a natural hormone produced by the gut when it's full, prompting the brain to reduce feeding behavior.

Cone's team explored how these GLP-1 drugs interact with the melanocortin system. They conducted experiments in mouse models, manipulating the melanocortin system by inhibiting melanocortin 3 or boosting melanocortin 4 activity. Their findings revealed that adjusting these proteins made the mice more responsive to GLP-1 drugs and other hormones that influence feeding behavior. Mice receiving a combination of a GLP-1 drug with an MC4R agonist or MC3R antagonist exhibited significantly greater weight loss and reduced feeding compared to those receiving only the GLP-1 drugs.

Cone noted that activating the central melanocortin system heightened the animals' sensitivity not just to GLP-1 drugs but to all tested anti-feeding hormones. Importantly, they observed no increased nausea response when GLP-1 drugs were combined with modifications to the melanocortin system, suggesting potential for enhancing drug effectiveness without exacerbating unwanted side effects.

While the research was conducted in mouse models, Cone expressed optimism about the potential translatability of these findings to humans, given the conservation of the melanocortin system across species. Further research and clinical trials will be necessary to validate these findings and explore potential applications in human medicine.

This study was supported by funding from the National Institutes of Health and Courage Therapeutics.


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