Oral GLP-1 Drugs May Quiet the Brain’s Food Craving Circuit
New NIH-funded research reveals that oral small-molecule GLP-1 drugs, like orforglipron, may reduce pleasure-driven eating by directly affecting a reward circuit in the brain's central amygdala, distinct from known appetite pathways.
Popular weight-loss and diabetes medications such as semaglutide and Ozempic belong to a broader group known as GLP-1 drugs. A study funded by the National Institutes of Health (NIH) has now identified a previously unrecognized way that some newer oral drugs in this class may affect the brain.
The University of Virginia team studied small-molecule GLP-1 receptor agonists. These compounds differ from larger peptide medications such as semaglutide, which is used in well-known drugs including Ozempic, Wegovy, and Rybelsus. The researchers focused on orforglipron, a Food and Drug Administration (FDA)-approved oral medication, as well as the experimental small-molecule drug danuglipron. Oral compounds of this kind can be taken as pills and may cost less to manufacture than injectable GLP-1 drugs.
To investigate, the researchers used gene-editing techniques to modify GLP-1 receptors in mice, making the receptors more similar to those found in humans. The team gave the mice either orforglipron or danuglipron and then examined which parts of the brain became active. As expected, the drugs affected regions already associated with appetite regulation. However, they also activated the central amygdala, an area involved in desire and reward. Additional experiments showed that activation of the central amygdala reduced dopamine release in important parts of the brain's reward system while the mice were eating for pleasure.
"We've known that GLP-1 drugs suppress feeding behavior driven by energy demand. Now it seems oral small-molecule GLP-1s also dial back eating for pleasure by engaging a brain reward circuit," said co-corresponding author Ali Guler, Ph.D, a professor of biology at the University of Virginia.
Researchers now want to determine whether these next-generation medications can reduce cravings for substances other than food. Follow-up studies will specifically examine their possible effects on substance use disorder.
