summary: Modulating melanocortin proteins in the brain increases the effectiveness of GLP-1 diabetes and weight loss drugs: inhibiting MC3R or activating MC4R made mice more sensitive to these drugs, resulting in more pronounced weight loss and reduced food intake without additional side effects.
This discovery has the potential to improve 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 feeding behavior and energy balance.
- Improved drug susceptibility: Modulating these proteins increases the effectiveness of GLP-1 drugs by up to five-fold.
- Potential applications in humans: The findings in mice could lead to improved treatments for diabetes and obesity in humans.
sauce: University of Michigan
Harnessing a network of proteins in the central nervous system could make common diabetes and weight-loss drugs more effective and reduce their side effects, according to a new study from the University of Michigan.
The study was published today Clinical Research Journalfocused on two proteins, melanocortin 3 and melanocortin 4, which are found 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.
Melanocortin 3 and melanocortin 4 influence everything from sensing long-term energy stores to processing signals from the gut about short-term satiety and fullness, said Roger Cohn, a physiologist at the University of Michigan who led the study.
A group of drugs known as GLP-1 agonists, which include semaglutide (e.g. Ozempic) and tirzepatide (e.g. Munjaro), have recently attracted a lot of attention for their potential to treat not only type 2 diabetes, but also obesity, heart disease and potentially addiction. These drugs work by mimicking a natural hormone produced by the gut when it is full, prompting the brain to reduce eating behaviour.
“So the obvious question for us was, how do these GLP-1 drugs, which work by manipulating satiety signals, prime the melanocortin system?” said Cohn, a professor of molecular and integrative physiology in the U-M School of Medicine and director of the U-M Institute for Life Sciences, where his lab is located.
Cohn and his colleagues tested the effects of several hormones that reduce food intake in mouse models. They compared the results in normal mice and mice that genetically lacked the MC3R protein, mice that were given a chemical that inhibited MC3R activity, and mice that were given a drug that enhanced MC4R activity. (MC3R is a natural negative regulator of MC4R, decreasing MC4R activity, so inhibiting MC3R and enhancing MC4R activity have similar effects.)
In both cases, the study’s lead author Naima Dahir, a postdoctoral researcher in the Cohn 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 an MC3R antagonist showed up to five-fold greater weight loss and reduced food intake than mice that received the GLP-1 drug alone.
“We found that activating the central melanocortin system made animals hypersensitive to the effects of not only GLP-1 but every anorectic hormone that we tested,” Cohn said.
The researchers also measured activity in parts of the brain thought to cause nausea in response to GLP-1 drugs, and observed that combining GLP-1 drugs with changes to the melanocortin system showed no increase in activity.In contrast, priming melanocortin neurons led to a significant increase in GLP-1 drug-induced activity in neurons in the feeding center of the hypothalamus of the brain.
The findings indicate that combining an existing GLP-1 drug with an MC4R agonist can increase sensitivity to the drug’s desired effects by up to five-fold, without increasing unwanted side effects.
Ultimately, this approach may allow side-effect-sensitive patients to be treated with lower doses and improve outcomes for patients who do not respond to existing doses of the medication. Further drug development and clinical trials are needed to realise this.
Although the study was only conducted in a mouse model, Kohn is optimistic that the results will translate well to humans.
“The melanocortin system is highly conserved in humans,” he said. “Everything we’ve observed studying these proteins in mice over the last few decades has also been found in humans, and we think these results may be applicable to patients.”
The research was funded by the National Institutes of Health and Courage Therapeutics.
Study authors are Naima Dahir, Yijun Gui, Yanan Wu, Alix Rouault, Savannah Williams, Luis Gimenez, Stephen Joy, Anna K. Mapp and Roger Cone of the University of Michigan, Patrick Sweeney of the University of Illinois and Tomi Sawyer of Courage Therapeutics.
About this Neuropharmacology Research News
author: Morgan Sherburne
sauce: University of Michigan
contact: Morgan Sherburne – University of Michigan
image: Image courtesy of Neuroscience News
Original Research: Open access.
“Subthreshold activation of the melanocortin system induces systemic sensitization to appetite suppressants in miceRoger Cohn et al. JCI
Abstract
Subthreshold activation of the melanocortin system induces systemic sensitization to appetite suppressants in mice
The melanocortin 3 receptor (MC3R) controls GABA release from agouti-related protein (AgRP) nerve terminals, tonically inhibiting multiple circuits involved in feeding behavior and energy homeostasis.
Here, we investigated the role of MC3R and the melanocortin system in regulating responses to various appetite suppressants.
Genetic deletion or pharmacological inhibition of MC3R or subthreshold administration of MC4R agonists improved dose-responsiveness to glucagon-like peptide 1 (GLP1) agonists as assessed by inhibition of food intake and weight loss.
Enhanced anorectic responses to the acute satiety factors peptide YY (PYY3-36) and cholecystokinin (CCK) and the long-term adipose inhibitor leptin demonstrated that increased sensitivity to anorectic drugs is a general consequence of MC3R antagonism.
After administration of low-dose liraglutide to MC3R-KO mice, we observed enhanced neural activity in multiple hypothalamic nuclei using Fos IHC (Mac–/–), supporting the hypothesis that MC3R is a negative regulator of circuits controlling various aspects of feeding behavior.
Enhanced appetite suppression response Mac–/– The degree of obesity in mice after GLP1 analog administration was independent of the incretin effects and fatigue induced by GLP1 receptor (GLP1R) analogs, suggesting that MC3R antagonists or MC4R agonists may be of value in expanding the dose-response range for the treatment of obesity.
