On May 6, 2026, In a study published in Nature, a team led by University of Virginia (UVA) neuroscientist Ali D. Güler found that a new class of oral GLP-1 drugs can directly influence brain circuits tied to reward and motivation, not just hunger, meaning they have the ability to reshape not just appetite but the desire for food itself — an effect that could help explain both the drugs’ success and their more puzzling side effects.

GLP-1 drugs were originally developed to treat Type 2 diabetes by improving insulin response, and their weight-loss effects were initially considered a side benefit. Güler’s team wanted to dig a little deeper into how the drug worked, focusing on not just its affect on insulin but on what else it might be doing in the body.

Using a unique, genetically engineered mouse model, the researchers demonstrated that newer small-molecule GLP-1 drugs — such as recently approved oral medications — can reach deep regions of the brain. Scientists have long understood that these drugs act on neurons in the hindbrain, a region that helps regulate basic functions and contributes to feelings of fullness and nausea. The UVA team found that, in addition to those established effects, the drugs also engage a separate circuit linking the hindbrain to the central amygdala, which is involved in processing emotions, and ultimately to dopamine-producing neurons. That pathway plays a critical role in how the brain assigns value to rewarding experiences like eating high-calorie foods.

“What we show is that these drugs can reduce not just hunger, but the desire to pursue rewarding food,” Güler said. “They’re acting on the system that makes you want the cake, not just the system that makes you feel full.” The findings also help explain differences among drugs in this rapidly growing class. Some compounds appear to produce more nausea-like effects, while others create a distinct brain state that reduces food motivation without the same level of discomfort.

Early evidence also suggests some patients find it easier to quit smoking or curb other compulsive behaviors while on GLP-1 drugs. Others report a diminished sense of enjoyment from eating. Güler sees both sides as reason for deeper investigation. As GLP-1 drugs become more widely used, researchers say a deeper understanding of their neurological effects will be essential, not only to improve their effectiveness, but also to anticipate how they may shape behavior and well-being over time.