Research Reveals Method to Improve Diabetes and Weight-Loss Drug Performance

According to new research from the University of Michigan, a network of proteins found in the central nervous system could be leveraged to enhance the effectiveness and minimize the side effects of popular diabetes and weight-loss medications.

The study, published in the Journal of Clinical Investigation, focused on two proteins, melanocortin 3 and melanocortin 4, primarily located on the surface of neurons in the brain.

These proteins play a central role in regulating feeding behavior and maintaining the body's energy balance.Melanocortin 3 and 4 influence everything from sensing long-term energy stores to processing gut signals about short-term satiety.

GLP-1 agonists, such as semaglutides (e.g., Ozempic) and tirzepatides (e.g., Mounjaro), have gained attention for effectively treating type 2 diabetes, obesity, heart disease, and potentially addiction. These drugs mimic a natural hormone produced by the gut when full, signaling the brain to reduce feeding behavior.

In the study, researchers tested the effects of several hormones that reduce food intake in the mouse models and discovered that modifying the melanocortin system made mice more responsive to GLP-1 drugs and other hormones influencing feeding behavior. Mice treated with a combination of a GLP-1 drug and an MC4R agonist or MC3R antagonist experienced up to five times more weight loss and reduced feeding compared to those receiving only GLP-1 drugs.

The researchers also measured brain activity in areas associated with nausea from GLP-1 drugs and found no increased activation when these drugs were combined with alterations to the melanocortin system. However, priming melanocortin neurons significantly boosted GLP-1 drug activation in hypothalamic feeding centers.

The findings suggested that combining GLP-1 drugs with an MC4R agonist could increase the drugs' effectiveness by up to fivefold without enhancing side effects. This approach could allow patients sensitive to side effects to take lower doses or improve outcomes in those unresponsive to current dosages. Further drug development and clinical testing are needed to advance this strategy.

Although this research has only been conducted in mouse models, researchers remain optimistic that the results will translate effectively to humans.

"The melanocortin system is highly conserved in humans. 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,” said Cone, director of the U-M Life Sciences Institute.

Reference: Roger D. Cone, et al.; Subthreshold activation of the melanocortin system causes generalized sensitization to anorectic agents in mice; Journal of Clinical Investigation; Volume 134, Issue 14 on July 15, 2024; 134(14):e178250. https://doi.org/10.1172/JCI178250.