New therapy causes weight loss in mice by targeting appetite center

A groundbreaking article in Nature describes a promising new therapy for obesity that leads to greater weight loss in mice compared to existing drugs. The approach involves delivering molecules to the brain's appetite center and influencing the brain's neuroplasticity.

"I believe that the drugs available on the market today are the first generation of weight loss drugs. Now we have developed a new type of weight loss drug that affects brain plasticity and seems to be very effective."

That's 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 senior author of the new study published in the prestigious scientific journal Nature.

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

"The effect of GLP-1 in combination with these molecules is very strong. In some cases, mice lose twice as much weight as mice treated with GLP-1 alone," says Clemmensen.

This means that future patients could achieve the same effect with a lower dosage. What's more, the new drug could become an alternative for 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 current weight-loss drugs, including nausea. But because the drug is so effective, we may be able to lower the dosage and thus reduce some side effects in the future – although we don't yet know how people will react to this drug," he adds.

Testing of the new weight loss drug is still at the so-called preclinical stage, which is based on studies with cells and experimental animals. The next step is clinical trials involving humans.

"We already know that drugs based on GLP-1 can lead to weight loss. The molecule we attached to GLP-1 affects the so-called glutamatergic neurotransmitter system, and in fact other studies in humans suggest that this family of compounds has significant potential for weight loss is what effect we get when we combine these two compounds into one drug,” emphasizes Clemmensen.

The drug must undergo three phases of clinical trials involving humans. According to Clemmensen, it could take eight years before the drug becomes available on the market.

The brain protects against excess body weight Clemmensen and his colleagues became interested in molecules that are used to treat chronic depression and Alzheimer's disease.

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

"This family of molecules may have permanent effects on the brain. Studies have shown that even relatively infrequent treatments can lead to lasting changes in brain pathology. We are also seeing 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 was probably to our benefit, as it meant we could survive periods of food shortage. Today, food shortages are not a problem in large parts of the world, where increasing numbers of the population suffer from obesity.

"Today, more than one billion people worldwide have a body mass index of 30 or more. This makes it increasingly important to develop drugs that will help manage this disease and help the body maintain a lower weight. We devote a lot of energy to this topic in our research," says Clemmensen.

Trojan horse delivers neuroplasticity modulators to appetite-regulating neurons We know that drugs based on the gut hormone GLP-1 effectively target a part of the brain that is key to weight loss, the appetite control center.

"What's exciting - at the cellular level - about this new drug is that it combines GLP-1 and molecules that block the NMDA receptor. It uses GLP-1 as a Trojan horse to deliver these small molecules exclusively to neurons, which influence appetite control. Without GLP-1, molecules targeting the NMDA receptor would affect the entire brain and thus would be nonspecific," says postdoc Jonas Petersen from Clemmensen's group, who is the first author of the study and the chemist who synthesized the molecules.

Non-specific drugs are often associated with serious side effects, as previously observed in drugs for the treatment of various neurobiological conditions.

"Many brain disorders are difficult to treat because drugs must cross what is called the blood-brain barrier. While large molecules such as peptides and proteins typically have difficulty accessing the brain, many small molecules have unrestricted access to the entire brain "We took advantage of GLP-1's specific access to the appetite control center in the brain to deliver one of these substances that would otherwise be nonspecific," says 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 to a whole new class of drugs to treat these conditions.", such as neurodegenerative diseases or mental disorders."