Researchers at the National Institutes of Health (NIH) have uncovered new details about how GLP-1 weight loss drugs such as semaglutide affect brain cells, revealing internal signaling processes that scientists have only begun to understand. The findings, based on experiments in mice, shed light on why these medications work differently from person to person and why their effects often slow down over time.
GLP-1 receptor agonists, including drugs like Ozempic and Wegovy, are already known to help reduce appetite and promote weight loss. Scientists have also identified the brain regions involved in those effects. Until now, however, much less was known about what happens inside the neurons targeted by these drugs.
“We know much less about the nuts and bolts of what goes on within the neurons that these medications target. By digging into these mechanisms, we’re beginning to answer some of these questions,” said co-corresponding author Andrew Lutas, Ph.D., an investigator at NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).
Brain Cell Signals Linked to Weight Loss
The research team used fluorescence imaging to monitor how semaglutide affected living brain tissue from mice. The work was led by first author Claire Gao, Ph.D., a postdoctoral fellow at NIH’s National Institute of General Medical Sciences (NIGMS).
By blocking or removing specific signaling molecules inside neurons, the scientists were able to determine which cellular pathways played the biggest role in weight loss effects.
Their experiments showed that semaglutide’s impact depended heavily on increased levels of cyclic adenosine monophosphate, or cAMP, in the area postrema, a part of the brain involved in appetite regulation. However, the response was not the same in every neuron.
“It was not an all or nothing phenomenon. We observed that cAMP responses across cells varied on a continuum,” said co-corresponding author Michael Krashes, Ph.D., a senior investigator at NIDDK.
Why Some GLP-1 Effects Fade Over Time
Researchers found that some neurons maintained elevated cAMP levels for longer periods while semaglutide was present. Other neurons showed only temporary increases. According to the authors, some cells may reduce their response by internalizing or breaking down GLP-1 receptors.
The team also tested whether they could prolong these signals. Using the drug roflumilast to block PDE4, an enzyme that breaks down cAMP, they were able to shift more neurons toward a longer lasting response.
The discovery raises the possibility that future GLP-1 treatments could remain effective for longer periods, potentially reducing how often patients need injections. Scientists also believe this type of cAMP modulation might eventually help people overcome the weight loss plateaus commonly reported with GLP-1 drugs. The researchers caution that much more study is needed before those possibilities can be confirmed.
Next Steps for GLP-1 Research
One limitation of the study was that researchers could only observe intracellular signaling in brain tissue for a few hours at a time. The team hopes to use newer techniques in future studies to track how GLP-1 drugs affect neurons over days or even weeks.
The findings offer a deeper look into the brain chemistry behind GLP-1 medications and may help guide the development of more effective weight loss treatments in the future.