A National Institutes of Health (NIH)-funded study found that an emerging class of GLP-1 weight-loss drugs inhibits pleasure eating, or hedonic eating, in mice by modulating reward circuits deep in the brain. This newly demonstrated pathway is distinct from previously described mechanisms that broadly affect appetite, and could provide a means for GLP-1 to treat other dysfunctions in reward processing, such as substance use disorders.
In this study, researchers at the University of Virginia specifically investigated small molecule GLP-1 receptor agonists, such as Food and Drug Administration (FDA)-approved orforglyprone. Orforglipron can be taken orally and is cheaper to manufacture than its injectable counterpart.
As the availability of these drugs increases and patient intake increases, it is important to understand the neural mechanisms underlying the effects we are seeing. ”
Lorenzo Reggio, MD, Clinical Director, NIH National Institute on Drug Abuse (NIDA)
Previous studies have extensively investigated the effects of larger peptides such as semaglutide, GLP-1, in the brain, and found that GLP-1 suppresses hunger-induced feeding by engaging networks in the hypothalamus and hindbrain. Until now, scientists didn’t have a very clear picture of how small molecule GLP-1 drugs worked.
To better understand this, the authors used gene editing techniques to modify the GLP-1 receptor in mice, making them more human-like.
The researchers administered orforglipron or another small molecule drug, danuglipron, and identified the brain regions where they triggered activity. While GLP-1 affected areas close to home, it also triggered activity in the central amygdala, a desire-related region of the brain deeper than scientists previously thought GLP-1 could directly reach.
Further experiments showed that activation of the central amygdala reduced dopamine release to a key hub in the brain’s reward circuitry during hedonic eating.
“GLP-1 drugs are known to suppress eating behaviors driven by energy demands. Now, oral small molecule GLP-1 appears to suppress eating for pleasure by engaging the brain’s reward circuitry,” said co-author Dr. Ali Guler, professor of biology at the University of Virginia.
The next logical question, the scientists say, is whether these next-generation GLP-1s can alleviate cravings for things other than food. In a follow-up study, the researchers hope to take a closer look at the effects, particularly on substance use disorders.
NIH is supported by National Institute of Neurological Disorders and Stroke (NINDS) grants R01NS111220, R01NS122834, and R01NS120702, National Institute of General Medical Sciences (NIGMS) grant R35GM140854, and National Heart, Blood, and Lung Institute (NHLBI) grant This research was supported through R01HL153916 and the National Cancer Center. National Institutes of Health (NCI) grant P30CA044579.
This study has not been completed as a clinical trial in connection with the application and has not been evaluated by the FDA for product approval for the indicated indication.
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National Institutes of Health (NIH)
Reference magazines:
Godshall, EN; others. (2026) Brain reward circuits inhibited by next-generation weight loss drugs in mice. Nature. DOI: 10.1038/s41586-026-10444-4. https://www.nature.com/articles/s41586-026-10444-4
