Scientists Develop ‘Trojan Horse’ Weight-Loss Drug That Targets Brain Plasticity

A revolutionary new weight-loss drug is targeting the brain’s plasticity in hopes of combatting obesity. Published in the journal Nature, the study demonstrates a novel use of the weight loss hormone GLP-1. By combining GLP-1 with specific molecules that block a receptor protein called the NMDA receptor, researchers from the University of Copenhagen have created a drug that acts as a “Trojan Horse,” delivering these molecules directly into the brain’s appetite control center.

“I consider the drugs available on the market today as the first generation of weight-loss drugs. Now we have developed a new type of weight-loss drug that affects the plasticity of the brain and appears to be highly effective,” says senior study author Christoffer Clemmensen, associate professor and group leader at the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen.

Brain plasticity, also known as neuroplasticity, refers to the brain’s ability to restructure itself by forming new neural connections. This adaptability allows the brain to adjust to new experiences, learn new skills, absorb information, and even recover from injuries. By targeting neuroplasticity, the new drug has the potential to induce lasting changes in the brain’s appetite control mechanisms.

In their study, researchers demonstrated that the combination of GLP-1 and NMDA receptor-blocking molecules had a powerful effect on weight loss in mice.

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

This means that future patients could potentially achieve the same weight loss results with lower dosages, which could help mitigate some of the side effects associated with current obesity treatments.

One of the most exciting aspects of this new drug is its ability to target specific areas of the brain.

“What is spectacular – on a 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 the neurons that affect appetite control. Without GLP-1, the molecules that target the NMDA receptor would affect the entire brain and thus be non-specific,” explains first study author Jonas Petersen, postdoctoral researcher from the Clemmensen Group and the chemist who synthesized the molecules.

This targeted approach is crucial because non-specific drugs that affect the entire brain often lead to severe side effects. By using GLP-1 as a vehicle to deliver the NMDA receptor-blocking molecules directly to the appetite control center, researchers have found a way to minimize potential adverse reactions.

While the new drug is still in the preclinical phase, which involves testing on cells and experimental animals, the researchers are optimistic about its potential. The next step is to conduct clinical trials with human participants, a process that could take up to eight years before the drug becomes available on the market.

The human body has evolved to defend a certain body weight and fat mass, which was likely advantageous from an evolutionary perspective, as it allowed our ancestors to survive periods of food scarcity. However, in today’s world, where over 1 billion people have a BMI of 30 or more, this protective mechanism has become a liability. Developing drugs that can help the body sustain a lower weight has become increasingly important in the fight against obesity.

Beyond its potential as a weight loss treatment, this new approach of using GLP-1 as a “Trojan Horse” to deliver targeted molecules to specific brain regions could have far-reaching implications.

“In this study, we have focused on obesity and weight loss, but in fact this is a completely new approach for delivering drugs to specific parts of the brain,” concludes Clemmensen. “So, I hope our research can pave the way for a whole new class of drugs for treating conditions like neurodegenerative diseases or psychiatric disorders.”

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