A revolutionary study published in Nature unveils a new therapy for obesity that results in greater weight loss in mice compared to current treatments. This innovative method involves transporting molecules into the brain’s appetite center, impacting its neuroplasticity.
“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.”
This statement comes from Associate Professor and Group Leader Christoffer Clemmensen from the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen, the senior author of the new study published in the renowned journal Nature.
In their research, Clemmensen and his team explore a novel application of the weight loss hormone GLP-1. This hormone can serve as a ‘Trojan Horse’ to deliver a specific molecule into the brains of mice, effectively altering brain plasticity and promoting weight loss.
“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.”
Christoffer Clemmensen, Associate Professor and Group Leader from the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen
This discovery suggests that future patients could achieve the same weight loss results with lower doses. Additionally, this new drug might 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 the weight loss drugs available on the market today, including nausea. But because the drug is so effective, we may be able to lower the dosage and thus mitigate some of the side effects in the future – though we still don’t know how humans respond to the drug,” he says.
The new weight loss drug is still in the preclinical phase, based on cell studies and animal experiments. The next step is clinical trials involving human participants.
“We already know that GLP-1-based drugs can lead to weight loss. The molecule that we have attached to GLP-1 affects the so-called 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 a single drug,” Clemmensen emphasizes.
The drug will undergo three phases of clinical trials with human participants, which could take up to eight years before it becomes available on the market.
The Brain’s Role in Defending Excessive Body Weight
Clemmensen and his colleagues became interested in molecules used to treat chronic depression and Alzheimer’s disease.
These molecules inhibit a receptor protein known as the NMDA receptor, which is crucial for long-term changes in brain connections and has garnered scientific interest in fields like learning and memory. Drugs targeting these receptors can strengthen or weaken specific nerve connections.
“This family of molecules can have a permanent effect on the brain. Studies have demonstrated that even a relatively infrequent treatment can lead to persistent changes to the brain pathologies. We also see molecular signatures of neuroplasticity in our work, but in this case in the context of weight loss,” Clemmensen explains.
The human body has evolved to maintain a certain body weight and fat mass, which historically helped humans survive food scarcity. However, in today’s world, where obesity is a growing issue, developing effective weight-loss drugs has become increasingly relevant.
“Today, more than one billion people worldwide have a BMI of 30 or more. This makes it increasingly relevant to develop drugs to aid this disease, and which can help the organism to sustain a lower weight. This topic is something we invest a lot of energy in researching,” says Clemmensen.
A Trojan Horse for Neuroplasticity Modulators
We know that drugs based on the intestinal hormone GLP-1 effectively target the brain’s appetite control center.
“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,” says Postdoc Jonas Petersen from the Clemmensen Group, the first author of the study and the chemist who synthesized the molecules.
Non-specific drugs often come with severe side effects, as seen in treatments for various neurobiological conditions.
“A lot of brain disorders are difficult to treat, because the drugs need to cross the so-called blood-brain barrier. Whereas large molecules like peptides and proteins generally have difficulties accessing the brain, many small molecules have unlimited access to the entire brain. We have used the GLP-1 peptide’s specific access to the appetite control center in the brain to deliver one of these otherwise non-specific substances to this region only,” Clemmensen says and adds:
“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. 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.”
