In mice, the medications reduced hedonic feeding, which means eating for enjoyment rather than because the body needs energy. The drugs appeared to do this by changing activity in a reward circuit located deep inside the brain.

This newly mapped pathway is separate from the appetite-control systems previously linked to drugs such as semaglutide. Researchers say it may also offer clues about whether GLP-1 medications could eventually be used to address other problems involving reward and craving, including substance use disorder.

Oral Alternatives to Injectable GLP-1 Drugs

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.

“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, M.D., Ph.D., Clinical Director of NIH’s National Institute on Drug Abuse (NIDA).

How Semaglutide and Other GLP-1 Drugs Affect Hunger

Scientists have already studied the effects of larger peptide GLP-1 drugs, such as semaglutide, extensively. Research has shown that these medications reduce hunger-driven eating by acting on networks in the hypothalamus and hindbrain.

Much less was known about what small-molecule oral GLP-1 drugs do after they enter the brain.

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.

A Surprising Signal Deep in the Brain

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.

This region lies deeper in the brain than scientists had previously thought GLP-1 drugs could reach directly.

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.

Turning Down the Reward of Food

“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.

The findings suggest that oral GLP-1 drugs may influence more than physical hunger. They may also weaken the pleasurable reward signals that make certain foods especially tempting.

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.

Funding and Regulatory Details

NIH supported this research through the National Institute of Neurological Disorders and Stroke (NINDS) grants R01NS111220, R01NS122834, and R01NS120702, the National Institute of General Medical Sciences (NIGMS) grant R35GM140854, the National Heart, Blood, and Lung Institute (NHLBI) grant R01HL153916, and the National Cancer Institute (NCI) grant P30CA044579.

This study was not completed as a clinical trial associated with an application and has not been assessed by FDA for product approval for stated indications.