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Groundbreaking New Weight Loss Drug Is More Effective Than Current Treatments

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Associate Professor Christoffer Clemmensen of the University of Copenhagen has developed a new type of weight loss drug that uses the hormone GLP-1 to deliver neuroplasticity-modulating molecules to specific areas of the brain, significantly improving weight loss in the mouse. This innovative approach could offer a powerful alternative to current treatments with fewer side effects and is now moving toward clinical trials.

A groundbreaking study published in Nature introduces a new treatment for obesity that surpasses the weight loss results of current drugs in mice. This method involves delivering molecules directly to the appetite control center of the brain, thereby influencing neuroplasticity.

A new weight loss drug uses the hormone GLP-1 to target areas of the brain that control appetite, potentially reducing side effects and improving effectiveness compared to existing drugs, with human trials underway.

“I consider the drugs available on the market today to be the first generation of weight loss drugs. We have now developed a new type of weight loss drug that affects brain plasticity and appears to be very effective.

This is according to Associate Professor and group leader Christoffer Clemmensen, from the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen, who is the lead author of the new study, published in the prestigious journal scientist. Nature.

In the study, Christoffer Clemmensen and colleagues demonstrate a new use of the weight loss hormone GLP-1. GLP-1 can be used as a “Trojan horse” to smuggle a specific molecule into the brains of mice, where it successfully affects brain plasticity and causes weight loss.

“The effect of GLP-1 combined with these molecules is very strong. In some cases, mice lost twice as much weight as mice treated with GLP-1 alone,” explains Christoffer Clemmensen.

This means that future patients will potentially be able to achieve the same effect with a lower dose. Additionally, the new drug could provide an alternative for those who do not respond well to existing weight loss medications.

“Our studies in mice show side effects similar to those experienced by patients treated with weight loss drugs available on the market today, including nausea. But because the drug is very effective, we may be able to reduce the dose and thus alleviate some side effects in the future – although we still don’t know how humans respond to the drug,” he says.

Tests of the new weight loss drug are still in the so-called preclinical phase, which is based on studies on cells and laboratory animals. The next step is clinical trials with human participants.

“We already know that GLP-1 drugs can cause weight loss. The molecule we attached to GLP-1 affects the glutamatergic neurotransmitter system, and in fact, other studies with human participants suggest that this family of compounds has significant weight loss potential. What is interesting here is the effect we get when we combine these two compounds into one drug,” emphasizes Christoffer Clemmensen.

The drug must undergo three phases of clinical trials on human participants. According to Christoffer Clemmensen, it may therefore take eight years before the drug can be available on the market.

The brain defends excessive body weight

Christoffer Clemmensen and his colleagues developed an interest in molecules used to treat chronic depression and

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The molecules block a receptor protein called the NMDA receptor, which plays a key role in long-term changes in brain connections and has received scientific attention in the areas of learning and memory. Drugs targeting these receptors will strengthen and/or weaken specific nerve connections.

“This family of molecules can have a permanent effect on the brain. Studies have shown that even relatively infrequent treatment can lead to persistent changes in brain pathologies. We also see molecular signatures of neuroplasticity in our work, but here in the context of weight loss,” he explains.

The human body evolved to protect a certain body weight and body fat. From an evolutionary perspective, this has probably been to our advantage, because it means we have been able to survive periods of food scarcity. Today, food shortage is no longer a problem in much of the world, where a growing share of the population suffers from obesity.

“Today, more than a billion people worldwide have a BMI of 30 or more. It is therefore increasingly relevant to develop drugs to combat this disease and which can help the body maintain a lower weight. This is a topic in which we invest a lot of energy in our research,” says Christoffer Clemmensen.

A Trojan horse smuggles small molecules that modulate neuroplasticity into appetite-regulating neurons

We know that medications based on the gut hormone GLP-1 effectively target the part of the brain critical for weight loss, namely the appetite control center.

“What is spectacular – at the cellular level – about this new drug is the fact that it combines GLP-1 and molecules that block the NMDA receptor. It exploits GLP-1 as a Trojan horse to smuggle these small molecules exclusively into neurons that affect appetite control. Without GLP-1, molecules that target the NMDA receptor would affect the entire brain and would therefore be nonspecific,” explains postdoc Jonas Petersen of the Clemmensen group, first author of the study and chemist who synthesized the molecules.

Nonspecific drugs are often associated with serious side effects, which have been previously observed with drugs intended for the treatment of different neurobiological conditions.

“Many brain disorders are difficult to treat because medications must cross the blood-brain barrier. While large molecules like peptides and proteins generally have difficulty accessing the brain, many small molecules have unrestricted access to the entire brain. We used the specific access of the GLP-1 peptide to the appetite control center in the brain to deliver one of these otherwise non-specific substances to this region only,” explains Christoffer Clemmensen and adds:

“In this study we focused on obesity and weight loss, but this is actually a completely new approach to delivering drugs to specific parts of the brain. So I hope that our research can pave the way for a whole new class of drugs to treat diseases such as neurodegenerative diseases or psychiatric disorders.

Reference: “GLP-1-directed NMDA receptor antagonism for the treatment of obesity” by Jonas Petersen, Mette Q. Ludwig, Vaida Juozaityte, Pablo Ranea-Robles, Charlotte Svendsen, Eunsang Hwang, Amalie W. Kristensen, Nicole Fadahunsi, Jens Lund, Alberte W. Breum, Cecilie V. Mathiesen, Luisa Sachs, Roger Moreno-Justicia, Rebecca Rohlfs, James C. Ford, Jonathan D. Douros, Brian Finan, Bryan Portillo, Kyle Grose, Jacob E. Petersen, Mette Trauelsen, Annette Feuchtinger, Richard D. DiMarchi, Thue W. Schwartz, Atul S. Deshmukh, Morten B. Thomsen, Kristi A. Kohlmeier, Kevin W. Williams, Tune H. Pers, Bente Frølund, Kristian Strømgaard, Anders B. Klein and Christoffer Clemmensen, May 15, 2024, Nature.
DOI: 10.1038/s41586-024-07419-8

Christoffer Clemmensen, together with postdoc Jonas Petersen and a former University of Copenhagen scientist (Anders Klein), co-founded the biotechnology company Ousia Pharma, which is a spin-off company from the University of Copenhagen. The company continues to develop the medical concept presented in this study for the treatment of severe obesity.

News Source : scitechdaily.com
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