A National Institutes of Health (NIH)-funded study has revealed that a new generation of GLP-1 weight-loss drugs may do more than curb appetite — they appear to suppress “eating for pleasure” by targeting a deep brain reward circuit in mice.

 

Researchers report that small-molecule GLP-1 receptor agonists, including the oral drug orforglipron, influence a neural pathway that regulates hedonic feeding, a mechanism distinct from the well-known appetite control systems previously linked to GLP-1 therapies. 

 

The findings suggest these drugs could eventually help address other reward-related disorders, including substance use disorder.

 

“As the accessibility of these medications continues to rise and patient uptake increases, it’s crucial that we understand the neural mechanisms underlying the effects we’re seeing,” said Lorenzo Leggio, clinical director of NIH’s National Institute on Drug Abuse (NIDA).

 

Until now, most brain research on GLP-1 drugs has focused on larger peptide-based versions such as semaglutide, which reduce hunger-driven eating by acting on the hypothalamus and hindbrain. The mechanisms behind smaller, oral compounds have remained largely unclear.

 

In the new study, scientists at the University of Virginia used gene-editing techniques to modify GLP-1 receptors in mice to make them more humanlike. They then administered either orforglipron or another oral compound, danuglipron, tracking brain activity in response.

 

The drugs activated expected appetite-related regions — but also a surprising target: the central amygdala, a deeper brain structure associated with desire and reward processing.

 

Researchers say this is farther into the brain than GLP-1 drugs were previously thought to directly influence.

 

Once activated, the central amygdala was found to reduce dopamine release in key reward circuits during hedonic feeding, effectively dampening the pleasure response linked to eating.

 

“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, a professor of biology at the University of Virginia.

 

Scientists say the discovery opens the door to a broader question: whether these drugs could also reduce cravings for other rewarding substances beyond food. Future studies will explore potential implications for substance use disorder.