Future anti-obesity drugs like Wegovy may melt the weight away — but they can also cause unbearable nausea. Now scientists have identified a brain pathway involved in this common side effect, raising the prospect of effective weight loss drugs without unpleasant side effects 1.

The scientists found that the brain circuit that causes nausea, which also has a Aversion to food triggers, is separate from the circuit that helps the medication create the feeling of satiety, the feeling of fullness that prevents people from eating more.

"The implication is that we can now selectively target the satiety circuits without targeting the aversion circuits. We could potentially develop better drugs with fewer side effects," says Amber Alhadeff, a neuroscientist at the Monell Chemical Senses Center in Philadelphia, Pennsylvania and co-author of the study published today in theNaturewas published.

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Drugs like Wegovy mimic a hormone called glucagon-like peptide 1 (GLP-1), which controls blood sugar levels and acts on the brain to reduce appetite 2. (Wegovy and the diabetes drug Ozempic are brand names for Semaglutide, which is manufactured by Novo Nordisk, based in Bagsværd, Denmark.) Several regions of the brain have GLP-1 receptors, but which specific receptor populations are involved in the drugs' effects is not fully understood.

To clarify this uncertainty, Alhadeff and her colleagues first killed neurons with GLP-1 receptors in specific brain regions of mice. They then gave the mice a GLP-1 mimicking drug: either semaglutide or exenatide, which also has decreasing effects.

Mice lacking GLP-1 neurons in a region called the brainstem ate normally. This showed that the effects of the drugs had been completely blocked. But the drugs still worked after the researchers killed the GLP-1 neurons in the brain region called the hypothalamus, which is important in appetite regulation and thought to be responsible for the GLP-1 drugs' effect. “We were shocked,” says Alhedeff. “The bottom line is that the brainstem is really the primary site of action of the drugs.”

The researchers then examined two subregions of the brainstem, the Area postrema (AP) and the Nucleus of the Nucleus Solitarius (NTS). When the scientists turned on the animals' AP neurons, the mice exhibited nausea and food aversion and reduced their food intake. In contrast, in mice whose NTS neurons were activated, the animals switched back when eating - but showed no signs of nausea.

This means that nausea is not necessary for GLP-1 drugs to suppress food intake. That's one of the study's most important points, says Martin Myers, a neuroscientist at the University of Michigan in Ann Arbor. “If there was a way to turn on just the NTS GLP-1 receptor neurons, or all the other GLP-1 receptor neurons, and just avoid those in the AP, that would certainly be a much better drug,” he says. “The real difficulty, of course, is how to do it.”