Scientists Flip the Brain’s “Fat-Off” Switch – Weight Loss Without Side Effects

Scientists have discovered a specific set of brain cells responsible for the weight loss effects of semaglutide, a popular drug for obesity and type 2 diabetes.

By isolating these neurons, researchers induced similar results without the drug – appetite reduction and fat loss – and found these benefits were disconnected from the drug’s unpleasant side effects like nausea and muscle loss. This breakthrough could pave the way for targeted treatments that deliver the benefits of semaglutide with fewer downsides.

Semaglutide: A Powerful But Imperfect Treatment

Semaglutide, a medication already widely used to treat obesity and type 2 diabetes, has gained attention for its ability to reduce hunger and help people lose weight. It belongs to a class of drugs known as GLP-1 receptor agonists and works by mimicking natural signals in the body that control appetite. However, like many medications, it can come with side effects such as nausea and muscle loss.

Now, researchers at the Sahlgrenska Academy at the University of Gothenburg have made a breakthrough. In a new study published in Cell Metabolism, they’ve identified a specific group of nerve cells in the brain that drive semaglutide’s weight-loss benefits, without triggering its common side effects.

Activated Nerve Cells Behind Semaglutide’s Effects

To understand how semaglutide works in the brain, scientists used mice to trace the drug’s effects on nerve cells. They pinpointed which neurons were activated by the drug, then stimulated those same cells directly, without using the drug itself.

The results were striking. The mice ate less and lost weight, just as they did with semaglutide treatment. But when those nerve cells were removed, the drug’s effects on appetite and fat reduction dropped off sharply. Meanwhile, side effects like nausea and muscle loss still occurred.

“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.

Unlocking Brain Mechanisms and Future Applications

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.

Reference: “Semaglutide effects on energy balance are mediated by Adcyap1+ neurons in the dorsal vagal complex” by Júlia Teixidor-Deulofeu, Sebastian Blid Sköldheden, Ferran Font-Gironès, Andrej Feješ, Johan Ruud and Linda Engström Ruud, 22 May 2025, Cell Metabolism.
DOI: 10.1016/j.cmet.2025.04.018

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