Brainstem Neurons Hold Key to Semaglutide's Weight Loss Effects

Summary: Researchers have identified a specific group of brainstem neurons that mediate the appetite-reducing and weight-loss effects of semaglutide without triggering side effects like nausea. In mice, activating these neurons led to reduced food intake and fat loss, mimicking the drug’s benefits.

Conversely, disabling them diminished semaglutide’s effects on weight, but not its adverse symptoms. This discovery could lead to more targeted obesity treatments that preserve the benefits of GLP-1R agonists while minimizing discomfort.

Key Facts:

• Targeted Neurons: A specific set of neurons in the dorsal vagal complex mediate semaglutide’s appetite-suppressing effects.
• Side Effect Separation: These neurons are not significantly involved in side effects like nausea or muscle loss.
• Therapeutic Potential: Targeting these neurons could enhance obesity treatments while reducing unwanted symptoms.

Source: University of Gothenburg

A specific group of nerve cells in the brain stem appears to control how semaglutide affects appetite and weight – without causing nausea.

The discovery, made at the University of Gothenburg, could pave the way for better drugs to treat obesity.

Semaglutide belongs to a group of drugs called GLP-1R agonists and has been shown to effectively reduce food intake and body weight. The drug is already well established as part of the treatment for obesity and type 2 diabetes, but can cause side effects such as nausea and muscle loss.

In a new study, researchers at the Sahlgrenska Academy at the University of Gothenburg have shown that it is possible to distinguish the nerve cells in the brain that control the beneficial effects – such as reduced food intake and fat loss – from those that contribute to side effects.

The study is published in the journal Cell Metabolism.

Activated nerve cells

To investigate how semaglutide affects the brain, the researchers worked with mice. They tracked which nerve cells were activated by the drug and were then able to stimulate these cells – without administering the drug itself.

The result was that the mice ate less and lost weight, just as they did when treated with semaglutide. When these nerve cells were killed, the drug’s effect on appetite and fat loss instead decreased significantly. However, side effects such as nausea and muscle loss remained.

“This suggests that these nerve cells control the beneficial effects of semaglutide. We have therefore identified a specific group of nerve cells that is necessary for the effects that semaglutide has on weight and appetite, but which does not appear to contribute to any significant extent to side effects such as nausea.

“If we can target the treatment there, we may be able to maintain the positive effects while reducing side effects,” says Júlia Teixidor-Deulofeu, first author of the study and PhD student at Sahlgrenska Academy at the University of Gothenburg.

The effect in the brain

The identified nerve cells are located in an area of the brain called the dorsal vagal complex. For the researchers, the result is not only an early step toward potentially improved treatment, it also provides new knowledge about how semaglutide works in the brain.

The study also provides deeper insight into how the brain stem regulates our energy balance.

“Semaglutide and other GLP-1R agonists are currently being prescribed to more and more people and are also being investigated for other potential indications such as substance use disorders and neurodegenerative diseases.

“It is important to understand how these drugs actually work. The better we understand this, the greater the opportunity we have to improve them,” says Linda Engström Ruud, researcher and supervisor to PhD students Júlia Teixidor-Deulofeu and Sebastian Blid Sköldheden, who both worked on the project.

About this semaglutide and neuroscience research news

Author: Júlia Teixidor-Deulofeu
Source: University of Gothenburg
Contact: Júlia Teixidor-Deulofeu – University of Gothenburg
Image: The image is credited to Neuroscience News

Original Research: Open access.
“Semaglutide effects on energy balance are mediated by Adcyap1⁺ neurons in the dorsal vagal complex” by Júlia Teixidor-Deulofeu et al. Cell Metabolism

Abstract

Semaglutide effects on energy balance are mediated by Adcyap1⁺ neurons in the dorsal vagal complex

The use of the GLP-1R agonist semaglutide is revolutionizing the treatment of obesity, yet its mechanistic effects on energy balance remain elusive.

Here, we demonstrate that reactivation of semaglutide-responsive dorsal vagal complex neurons mimics the drug’s effects of reducing food intake and body weight and promoting fat utilization and conditioned taste aversion.

We observe that many of the semaglutide-activated area postrema (AP) and nucleus of the solitary tract (NTS) neurons express Adcyap1 mRNA, and ablation of AP/NTS Adcyap1⁺ neurons largely reverses semaglutide’s effects on energy balance acutely in lean mice and in subchronically treated obese mice.

Semaglutide-activated AP/NTS Adcyap1⁺ neurons promote the loss of fat rather than lean mass, with only a modest effect on conditioned taste aversion.

Furthermore, NTS Adcyap1⁺ neurons are engaged by GLP-1R-expressing AP neurons and are necessary for semaglutide-induced activation of several downstream satiety-related structures.

Selective targeting of semaglutide-responsive Adcyap1⁺ neurons holds potential for improved future anti-obesity treatments.