A new study shows oral GLP-1 drugs suppress hedonic eating through a deep-brain reward circuit linked to dopamine release, potentially extending their use beyond weight loss.
Why do GLP-1 weight-loss drugs seem to quiet cravings in ways that go beyond simple appetite suppression? A new NIH-funded study suggests the answer may lie deep within the brain’s reward circuitry, where next-generation oral GLP-1 drugs appear to dampen “hedonic feeding” — eating motivated by pleasure rather than hunger.
The findings offer new insight into why these medications may influence compulsive behaviors more broadly, raising the possibility that they could eventually help treat conditions tied to addiction and reward processing.
Researchers at the University of Virginia investigated small-molecule GLP-1 receptor agonists, including the Food and Drug Administration (FDA)-approved drug orforglipron. Unlike widely used injectable GLP-1 therapies such as semaglutide, these newer compounds can be taken as pills and are less costly to manufacture, potentially making the rapidly growing class of medications more accessible to patients.
“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).
Researchers Compare Oral GLP-1s With Injectable Drugs
Earlier studies have largely focused on larger peptide-based GLP-1 drugs such as semaglutide. Those medications are known to reduce hunger-related eating by acting on regions of the hypothalamus and hindbrain. However, researchers have known far less about how smaller oral GLP-1 drugs affect the brain.
To investigate further, scientists used gene-editing methods to alter GLP-1 receptors in mice so they more closely resembled human receptors.
The researchers then gave the mice orforglipron or another small-molecule GLP-1 drug called danuglipron and mapped the brain regions activated by the treatments. In addition to affecting areas already linked to appetite control, the drugs also activated the central amygdala, a brain region tied to desire and reward that scientists did not previously believe GLP-1 drugs could directly access.
Central Amygdala Linked to Pleasure-Driven Eating
Additional experiments found that activation of the central amygdala lowered dopamine release in major parts of the brain’s reward system during hedonic feeding.
“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 say the next step is determining whether these newer GLP-1 drugs can also reduce cravings unrelated to food. Future studies will examine their potential effects on substance use disorder.
Reference: “A brain reward circuit inhibited by next-generation weight-loss drugs in mice” by Elizabeth N. Godschall, Taha Bugra Gungul, Isabelle R. Sajonia, Aleyna K. Buyukaksakal, Orien Li, Sophia Ogilvie, Austin B. Keeler, Guilian Tian, Yu Shi, Omar Koita, Chloe Xinzhu Guo, Tyler C. J. Deutsch, Eric J. Steacy, Maisie Crook, YuChen Zhang, Nicholas J. Conley, Gulsun Memi, Addison N. Webster, O. Yipkin Calhan, Weile Liu, Amani Akkoub, Karan Malik, Kaleigh I. West, Sara Michel-Le, Arun Karthikeyan, Grace van Gerven, Olivia A. Dell’Aglio, Kevin T. Beier, Larry S. Zweifel, Manoj K. Patel, John N. Campbell, Christopher D. Deppmann and Ali D. Güler, 6 May 2026, Nature.
DOI: 10.1038/s41586-026-10444-4
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.
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