“I consider the drugs available on the market today as the first generation of weight-loss drugs. Now we have developed a new weight-loss drug that affects the brain’s plasticity and appears highly effective.”

So says 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 senior author of the new study, which has been published in the prestigious scientific journal Nature.

Christoffer Clemmensen and colleagues demonstrated the use of a new weight loss hormone, GLP-1, in the study. GLP-1 can be used as a ‘Trojan Horse’ to smuggle a specific molecule into the brain of mice, where it successfully affects the brain’s plasticity and results in 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 explains.

This means that future patients can potentially achieve the same effect with a lower dosage. Moreover, the new drug may be an alternative to those who do not respond well to existing weight-loss drugs.

“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.

Testing the new weight loss drug is still in the so-called preclinical phase, based on studies with cells and experimental animals. The next step is clinical trials with 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,” Christoffer Clemmensen stresses.

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

What is neuroplasticity? The plasticity of the brain, also known as neuroplasticity, is the brain’s ability to restructure itself by forming new neural connections. This ability allows the brain to adjust to new experiences, learn new skills, absorb new information and recover from injuries. Neuroplasticity is found in several levels of the nervous system and can be anything from microscopic changes in the structure and function of individual neurons to major changes such as the formation of new neural connections or reorganisation of brain areas.

The brain defends against excessive body weight.

Christoffer Clemmensen and colleagues developed an interest in molecules that are used to treat chronic depression and Alzheimer’s disease.

The molecules block a receptor protein called the NMDA receptor. This receptor plays a key role in long-term changes in brain connections and has received scientific attention in the fields of learning and memory. Drugs targeting these receptors strengthen and/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 in brain pathologies. We also see molecular signatures of neuroplasticity in our work, but in this case, in the context of weight loss,” he explains.

The human body has evolved to protect a certain body weight and fat mass. From an evolutionary perspective, this has probably been to our advantage, as it means that we have survived periods of food scarcity. Today, food scarcity is not a problem in large parts of the world, where an increasing part of the population suffers from obesity.

“Today, over one billion people worldwide have a BMI of 30 or more. This makes it increasingly relevant to develop drugs to aid this disease, which can help the organism to sustain a lower weight. We invest a lot of energy in researching this topic,” says Christoffer Clemmensen.

A Trojan Horse smuggles small molecule modulators of neuroplasticity into appetite-regulating neurons.

We know that drugs based on the intestinal hormone GLP-1 effectively target the part of the brain that is key to weight loss, namely the appetite control centre.

“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, who is the first author of the study and the chemist who synthesized the molecules.

Non-specific drugs are often associated with severe side effects, which have previously been seen in drugs for treating different neurobiological conditions.

“A lot of brain disorders are difficult to treat because the drugs need to cross the so-called blood-brain barrier. Large molecules like peptides and proteins generally have difficulties accessing the brain, but many small molecules have unlimited access to the entire brain. We have used the GLP-1 peptide’s specific access to the appetite control centre in the brain to deliver one of these otherwise non-specific substances to this region only,” Christoffer 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.”