Popular weight loss and diabetes drugs 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 identified a previously unrecognized way in which some new oral drugs in this class may affect the brain.
In mice, the drug reduced hedonic eating, or eating for pleasure rather than because the body needs energy. The drug appears to do this by altering the activity of reward circuits deep in the brain.
This newly mapped pathway is separate from the appetite control system previously associated with drugs such as semaglutide. Researchers say this study may ultimately provide clues as to whether GLP-1 drugs can be used to solve other problems related to reward and craving, such as substance use disorders.
GLP-1 Oral alternative to injectable drugs
A team at the University of Virginia studied small molecule GLP-1 receptor agonists. These compounds differ from larger peptide drugs such as semaglutide, which are used in well-known drugs such as Ozempic, Wegovy, and Rybelsus.
The researchers focused on orforglipron, an oral drug approved by the Food and Drug Administration (FDA), and the experimental small molecule drug danuglipron. Because this type of oral compound can be taken as a tablet, it may be cheaper to manufacture than injectable GLP-1 drugs.
“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,” said Lorenzo Reggio, MD, clinical director of the NIH National Institute on Drug Abuse (NIDA).
Effects of semaglutide and other GLP-1 drugs on hunger
Scientists have already extensively studied the effects of larger peptide GLP-1 drugs, such as semaglutide. Research shows that these drugs reduce hunger-induced eating by acting on networks in the hypothalamus and hindbrain.
Little was known about how small molecule oral GLP-1 drugs work once they enter the brain.
To investigate, researchers used gene-editing techniques to modify the GLP-1 receptor in mice, making it more similar to the human receptor.
Surprising signals deep within the brain
The research team gave mice either orforglipron or danuglyprone and looked at which parts of the brain were activated.
As expected, the drug affected areas already involved in regulating appetite. But they also activated the central amygdala, an area associated with desire and reward.
This region lies deeper in the brain than scientists previously thought GLP-1 drugs could directly reach.
Additional experiments showed that while mice ate for pleasure, activation of the central amygdala reduced dopamine release in a key part of the brain’s reward system.
refuse food rewards
“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 results of this study suggest that oral GLP-1 drugs may have effects beyond physical hunger. It can also dampen the pleasurable reward signals that make certain foods particularly appealing.
Researchers now want to see whether these next-generation drugs can reduce cravings for substances other than food. Follow-up studies will specifically examine their possible impact on substance use disorders.
Funding and regulatory details
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.
