Resume: Modifying melanocortin proteins in the brain improves the effectiveness of GLP-1 diabetes and weight-loss drugs. By inhibiting MC3R or activating MC4R, mice showed increased sensitivity to these drugs, leading to more significant weight loss and eating less without additional side effects.
This discovery could improve treatment outcomes for patients taking GLP-1 drugs. Further research and clinical trials are needed to confirm these findings in humans.
Key Facts:
- Melanocortin proteins: MC3R and MC4R regulate eating behavior and energy balance.
- Increased sensitivity to drugs: By modifying these proteins, the effectiveness of GLP-1 drugs is increased by up to five times.
- Possible human application: Results in mice could lead to better treatments for diabetes and obesity in humans.
Source: University of Michigan
A network of proteins in the central nervous system could be harnessed to increase the effectiveness of popular diabetes and weight-loss drugs and reduce their side effects, new research from the University of Michigan shows.
The study, which appears today in the journal, Journal of Clinical Researchtargeting two proteins, called melanocortin 3 and melanocortin 4, which are found primarily on the surface of neurons in the brain and play a central role in regulating eating behavior and maintaining the body’s energy balance.
Melanocortin 3 and melanocortin 4 influence everything from sensing long-term energy stores to processing signals from the gut about short-term fullness or satiety, said Roger Cone, a physiologist at U-M who led the study.
The class of drugs known as GLP-1 agonists, which includes semaglutides (e.g., Ozempic) and tirzepatides (e.g., Mounjaro), have recently received a lot of attention for their effectiveness in treating not only type 2 diabetes, but also obesity, heart disease, and possibly addiction. They work by mimicking a natural hormone that the gut produces when it is full, which signals the brain to reduce eating behavior.
“So the obvious question for us was, how do these GLP-1 drugs, which work by manipulating satiety signals, function when we activate the melanocortin system?” said Cone, a professor of molecular and integrative physiology at the U-M Medical School and director of the U-M Life Sciences Institute, where his lab is based.
Working in mouse models, Cone and his colleagues tested the effects of different hormones that reduce food intake. They compared results in normal mice with mice genetically lacking the MC3R protein, in mice given chemicals to block MC3R activity, and in mice given a drug to increase MC4R activity. (Because MC3R is a natural negative regulator of MC4R, meaning it reduces MC4R activity, blocking MC3R and increasing MC4R activity have similar effects.)
In all cases, Naima Dahir, lead author of the study and a postdoctoral researcher in Cone’s lab, and her colleagues found that modifying the melanocortin system — by inhibiting MC3R or increasing the activity of MC4R — made the mice more sensitive to GLP-1 drugs and other hormones that influence eating behavior.
The mice given a GLP-1 drug in combination with an MC4R agonist or MC3R antagonist showed up to five times more weight loss and less eating behavior than mice given the GLP-1 drugs alone.
“We found that activating the central melanocortin system sensitizes animals not just to the effects of GLP-1s, but to every anti-feedant hormone we tested,” Cone said.
The researchers also measured activity in parts of the brain thought to cause nausea in response to GLP-1 drugs and saw no increased activation when GLP-1 drugs were combined with changes in the melanocortin system. In contrast, priming the melanocortin neurons significantly increased GLP-1 drug activation of neurons in hypothalamic feeding centers in the brain.
The findings show that combining existing GLP-1 drugs with an MC4R agonist can increase sensitivity to the desired effects of the drugs by up to five times, without increasing unwanted side effects.
Ultimately, this approach could allow patients who are sensitive to side effects to take a lower dose, or improve outcomes in patients who have not responded to existing drug dosages. Further drug development and clinical trials are needed before this can happen.
Although this research was only conducted in mouse models, Cone is optimistic that the results will also be applicable to humans.
“The melanocortin system is very well conserved in humans,” he said. “Everything we’ve seen in mice over the last few decades studying these proteins has been found in humans, so I suspect these results are translatable to patients as well.”
This research was funded by the National Institutes of Health and Courage Therapeutics.
The authors of the study are: Naima Dahir, Yijun Gui, Yanan Wu, Alix Rouault, Savannah Williams, Luis Gimenez, Stephen Joy, Anna K. Mapp, and Roger Cone, University of Michigan; Patrick Sweeney, University of Illinois; and Tomi Sawyer, Courage Therapeutics.
About this neuropharmacological research news
Author: Morgan Sherburne
Source: University of Michigan
Contact: Morgan Sherburne – University of Michigan
Image: The image is attributed to Neuroscience News
Original research: Open access.
“Subthreshold activation of the melanocortin system causes general sensitization to anorectic drugs in mice” by Roger Cone et al. JCI
Abstract
Subthreshold activation of the melanocortin system causes general sensitization to anorectic agents in mice
The melanocortin-3 receptor (MC3R) regulates GABA release from agouti-related protein (AgRP) nerve terminals, thereby suppressing multiple circuits involved in feeding behavior and energy homeostasis.
In this study, we investigated the role of the MC3R and the melanocortin system in regulating the response to different anorectic agents.
Genetic deletion or pharmacological inhibition of the MC3R, or subthreshold doses of an MC4R agonist, improved dose sensitivity to glucagon-like peptide 1 (GLP1) agonists, as evidenced by inhibition of food intake and weight loss.
An enhanced anorectic response to the acute satiety factors peptide YY (PYY3-36) and cholecystokinin (CCK) and the long-term adipostic factor leptin demonstrated that increased sensitivity to anorectic agents was a general consequence of MC3R antagonism.
We observed enhanced neuronal activation in multiple hypothalamic nuclei using Fos IHC after low-dose liraglutide in MC3R-KO mice (Mc3r–/–), supporting the hypothesis that the MC3R is a negative regulator of circuits that control multiple aspects of eating behavior.
The enhanced anorectic response in Mc3r–/– mice after administration of GLP1 analogs was also independent of the incretin effects and malaise induced by GLP1 receptor (GLP1R) analogs, suggesting that MC3R antagonists or MC4R agonists may be of value in improving the dose-response range of anti-obesity drugs.