Summary: Adjusting melanocortin proteins in the brain improves the effectiveness of GLP-1 drugs for diabetes and weight loss. By inhibiting MC3R or activating MC4R, mice showed increased sensitivity to these drugs, leading to greater weight loss and reduced feeding without additional side effects.
This discovery could improve treatment outcomes for patients using anti-GLP-1 drugs. Further research and clinical trials are needed to confirm these results in humans.
Highlights:
- Melanocortin proteins: MC3R and MC4R regulate feeding behavior and energy balance.
- Increased sensitivity to drugs: Adjusting these proteins increases the effectiveness of the GLP-1 drug up to five times.
- Human application potential: The results in mice could translate into better treatments for diabetes and obesity in humans.
Source: University of Michigan
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 a new study from the University of Michigan.
The study, published today in the Clinical Research Journalfocused on two proteins called melanocortin 3 and melanocortin 4 found primarily on the surface of neurons in the brain that play a central role in regulating feeding behavior and maintaining the body’s energy balance.
Melanocortin 3 and melanocortin 4 impact everything from sensing long-term energy stores to processing gut signals about short-term fullness or satiety, said UM physiologist Roger Cone, who led the study.
The class of drugs known as GLP-1 agonists, which includes semaglutides (eg, Ozempic) and tirzepatides (eg, Mounjaro), has recently received considerable attention for their effectiveness in treating not only type 2 diabetes, but also obesity, heart disease, and potentially drug addiction. They work by mimicking a natural hormone that the gut produces when it is full, prompting 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, work when we prime the melanocortin system?” said Cone, professor of molecular and integrative physiology in the UM School of Medicine and director of the UM Life Sciences Institute where his lab is located.
Working 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 those in mice that genetically lacked the MC3R protein, in mice that had been given chemicals to block MC3R activity, and in mice that had been given a drug to increase MC4R activity. (Because MC3R is a natural negative regulator of MC4R, meaning it decreases MC4R activity, blocking MC3R and increasing MC4R activity have similar effects.)
In any case, Naima Dahir, first author of the study and a postdoctoral researcher in Cone’s lab, and her colleagues found that tweaking 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 that received 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 the GLP-1 drugs alone.
“We found that activation of the central melanocortin system hypersensitizes animals to the effects of not only GLP-1, but all of the anti-feeding hormones we tested,” Cone said.
The researchers also measured activity in brain areas thought to trigger nausea in response to GLP-1 drugs and observed no increase in activation when GLP-1 drugs were combined with alterations in the melanocortin system. In contrast, priming melanocortin neurons significantly increased neuron activation by the GLP-1 drug in the brain’s hypothalamic feeding centers.
The results indicate that combining existing GLP-1 drugs with an MC4R agonist could increase sensitivity to the drugs’ desired effects by up to five-fold, without increasing unwanted side effects.
Ultimately, this approach could allow patients sensitive to side effects to take a lower dose, or could improve outcomes in patients who have not responded to existing drug dosages. Further drug development and clinical trials are needed before this is possible.
Although this research was only conducted in mouse models, Cone is optimistic that the results will be translatable 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 also been found in humans. So I think these findings could also be translated to patients.”
This research was funded by the National Institutes of Health and Courage Therapeutics.
The study authors 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 news on neuropharmacology research
Author: Morgan Sherburne
Source: University of Michigan
Contact: Morgan Sherburne – University of Michigan
Picture: Image credited to Neuroscience News
Original research: Free access.
“Subthreshold activation of the melanocortin system causes generalized sensitization to anorexic agents in mice” by Roger Cone et al. JCI
Abstract
Subthreshold activation of the melanocortin system induces generalized sensitization to anorexic agents in mice
The melanocortin-3 receptor (MC3R) regulates GABA release from agouti-related protein (AgRP) nerve terminals and thereby tonically suppresses several circuits involved in feeding behavior and energy homeostasis.
Here, we examined the role of MC3R and the melanocortin system in regulating the response to various anorexigenic agents.
Genetic deletion or pharmacological inhibition of MC3R, or subthreshold doses of an MC4R agonist, improved the dose responsiveness of glucagon-like peptide 1 (GLP1) agonists, as demonstrated by inhibition of food intake and weight loss.
An enhanced anorexic response to the acute satiety factors peptide YY (PYY3-36) and cholecystokinin (CCK) and the long-term adipostatic factor leptin demonstrated that increased sensitivity to anorexic agents was a generalized result 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 MC3R is a negative regulator of circuits that control multiple aspects of feeding behavior.
Enhanced anorexic response in Mc3r–/– Mice following GLP1 analogue administration were also independent of the incretin effects and malaise induced by GLP1 receptor (GLP1R) analogues, suggesting that MC3R antagonists or MC4R agonists may have value in improving the dose-response range of obesity therapies.