GLP-1 agonists: Addressing side effects of weight loss drugs

New research is uncovering how medications targeting the glucagon-like peptide-1 (GLP-1) system affect brain circuits involved in nausea, thirst, and pleasurable behaviors. These findings will be presented at Neuroscience 2025, the annual meeting of the Society for Neuroscience and the world’s largest source of emerging news about brain science and health.

Medications targeting the GLP-1 system are effective treatments for type 2 diabetes and obesity. GLP-1 drugs mimic a hormone that is naturally released in the gastrointestinal tract in response to eating and act in the brain to reduce hunger. However, these medications result in side effects like nausea and vomiting in up to 40% of people who take them, causing many patients to discontinue treatment. Researchers are investigating whether some of the adverse actions of GLP-1 drugs can be separated from their effects on weight loss, as well as potential other beneficial uses of these medications.

Today’s new findings show that:

• Combining low doses of the drug tirzepatide, a “dual agonist” that works, in part, by activating GLP-1 receptors, with the hormone oxytocin results in weight loss without gastrointestinal side effects in obese rats. (James E. Blevins, University of Washington)
• Nerve cells in the area postrema — the brain’s vomit center — are important for both  weight loss and nausea in response to GLP-1 drugs in mice. (Warren Yacawych, University of Michigan)
• In mice, activation of GLP-1 receptors on cells in the central amygdala activates a newly identified brain circuit that suppresses signals driving pleasure-based eating. (Ali D. Güler, University of Virginia)
• GLP-1 receptor agonists suppress thirst as well as appetite, and a region in the forebrain of rats called the median preoptic area appears to be involved in this effect. (Derek Daniels, University at Buffalo)

“Research demonstrates an effect of these medications on the brain beyond treating diabetes and obesity, via mechanisms that are still not fully understood,” says Lorenzo Leggio, MD, PhD, a physician-scientist and clinical director of the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health. “GLP-1 therapies appear to have multiple synergistic effects that may be useful for treating chronic diseases with overlapping neural mechanisms, including binge eating disorders and addictive disorders.”

This research was supported by national funding agencies including the National Institutes of Health (NIH), Department of Veterans Affairs (VA), and private funding organizations. This content is the sole responsibility of the authors and does not necessarily reflect the views of NIH or VA. For complete access to Neuroscience 2025 in person and online, request media credentials.