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Associate Professor Christopher Clemmensen from the University of Copenhagen has developed a new type of weight-loss drug that uses the hormone GLP-1 to deliver neuroplasticity-regulating molecules to specific brain regions, significantly promoting weight loss in mice. This innovative approach has the potential to be a powerful alternative to current treatments with fewer side effects and is currently progressing toward clinical trials.
Innovative research published in Nature We have introduced a new obesity treatment that exceeds the weight loss results of current drugs in mice. This method delivers molecules directly to the brain’s appetite control centers, influencing neuroplasticity.
A new weight loss drug uses the hormone GLP-1 to target brain regions that control appetite, potentially reducing side effects and improving effectiveness compared to existing drugs, with human trials pending. be.
“I believe that the drugs on the market today are the first generation of weight loss drugs. We now have a new type of weight loss drug that affects brain plasticity and appears to be highly effective. Developed.
says Christopher Clemmensen, associate professor and group leader at the Novo Nordisk Foundation Basic Metabolic Research Center at the University of Copenhagen. He is the senior author of a new study published in a prestigious scientific journal. Nature.
In this study, Christopher Clemensen and colleagues demonstrate a new use of the weight loss hormone GLP-1. GLP-1 is used as a “Trojan horse” to smuggle certain molecules into mouse brains, where they can affect brain plasticity and result in weight loss.
“The effect of the combination of GLP-1 and these molecules is very strong. In some cases, mice lose twice as much body weight compared to mice treated with GLP-1 alone,” says Christopher Clemensen. He explains.
This means future patients may be able to achieve the same effect with lower doses. Additionally, the new drug could serve as an alternative for people who don’t respond well to existing weight-loss drugs.
“Our studies in mice show side effects similar to those experienced by patients treated with currently marketed weight loss drugs, such as nausea. However, this drug is highly effective. “So we may be able to lower the dose in the future and reduce some of the side effects, but we don’t yet know how humans will respond to this drug,” he says.
Testing of new weight loss drugs is still in the so-called preclinical stage, which is based on research using cells and laboratory animals. The next step is clinical trials with human participants.
“We already know that GLP-1-based drugs can lead to weight loss. The molecules we have attached to GLP-1 affect the so-called glutamatergic neurotransmitter system and actually , other studies in human participants suggest that this group of compounds has the potential for significant weight loss.What’s interesting here is that these two compounds are combined into one drug. ”, emphasizes Christopher Clemensen.
The drug must undergo three stages of clinical trials on human participants. Therefore, it could take eight years for the drug to reach the market, according to Christopher Clemmensen.
the brain protects against excess weight
Christopher Clemensen and his colleagues were interested in molecules used to treat chronic depression. Alzheimer’s disease disease.
This molecule blocks receptor proteins called NMDA receptors. NMDA receptors play an important role in long-term changes in brain connectivity and have attracted scientific attention in the fields of learning and memory. Drugs that target these receptors can strengthen or weaken specific nerve connections.
“This family of molecules can have lasting effects on the brain. Research has demonstrated that even relatively infrequent treatments can produce lasting changes in brain pathology. “Our research also shows molecular signatures of neuroplasticity, but in this case in the context of weight loss,” he explains.
The human body has evolved to maintain a certain weight and fat mass. From an evolutionary perspective, this probably gave us an advantage, meaning we were able to survive times of food scarcity. Today, food insecurity is not a problem in most parts of the world, and the number of people suffering from obesity is increasing.
“Currently, more than one billion people around the world have a BMI of 30 or more. This makes it increasingly important to develop drugs that can treat this disease and help the organism lose weight.” The theme is one that we put a lot of energy into researching,” says Christopher Clemensen.
Trojan horses smuggle small molecule modulators of neuroplasticity into appetite-regulating neurons
Drugs based on the gut hormone GLP-1 have been shown to effectively target the part of the brain that is key to weight loss: the appetite control center.
“What’s amazing about this new drug at the cellular level is the fact that it combines molecules that block GLP-1 and NMDA receptors. It exploits GLP-1 as a Trojan horse and uses these small molecules to control appetite. “Without GLP-1, molecules that target NMDA receptors would affect the whole brain and would be nonspecific.” said author Jonas Petersen, a postdoctoral researcher at the Clemensen Group and the chemist who synthesized the molecule.
Non-specific drugs are often associated with serious side effects, which have been seen with drugs treating a variety of neurobiological conditions.
“Many brain diseases are difficult to treat because drugs have to cross the so-called blood-brain barrier. Large molecules such as peptides and proteins generally have difficulty accessing the brain, but many small molecules We took advantage of the specific access of the GLP-1 peptide to the appetite control center of the brain and delivered one of these non-specific substances only to this region. ” said Christopher Clemensen, adding:
“While this study has focused on obesity and weight loss, this is actually a completely new approach to delivering drugs to specific parts of the brain. We hope that this can pave the way for entirely new classes of drugs to treat conditions such as degenerative and psychiatric disorders.”
Reference: “GLP-1-directed NMDA receptor antagonism for obesity treatment” Jonas Petersen, Mette Q. Ludwig, Vaida Juozaityte, Pablo Ranea-Robles, Charlotte Svendsen, Eunsang Hwang, Amalie W. Kristensen, Nicole Fadahunsi, By Jens Lund, Alberte W. Bluhm, Cecily V. Matthiessen, Luisa Sachs, Roger Moreno Justicia, Rebecca Rolfs, James C. Ford, Jonathan D. Dulos, Brian Finan, Brian Portillo, Kyle Gross, Jacob E. Petersen, Mette Trauelsen, Annette Feuchtinger, Richard D. DiMarchi, Too W. Schwartz, Atul S. Deshmukh, Morten B. Thomsen, Christy A. Kohlmeier, Kevin W. Williams, Tune H. Peirce , Bente Frölund, Christian Stromgaard, Anders B. Klein, Christopher Clemmensen, 15 May 2024 Nature.
DOI: 10.1038/s41586-024-07419-8
Christopher Clemensen co-founded the biotechnology company Ousia Pharma, a spin-out from the University of Copenhagen, with postdoctoral fellow Jonas Petersen and former University of Copenhagen scientist Anders Klein. The company continues to develop the medical concept presented in this study for the treatment of severe obesity.
