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 are only beginning to understand. The findings, based on experiments in mice, shed light on why these drugs work differently for different people and why their effects often slow over time.
GLP-1 receptor agonists, such as Ozempic and Wegovy, are already known to suppress appetite and promote weight loss. Scientists have also identified brain regions involved in those effects. However, until now, little was known about what happens inside the neurons targeted by these drugs.
“We know very little about what happens within the neurons that these drugs target, and a closer look at these mechanisms is beginning to answer some of these questions,” said co-author Dr. Andrew Lutas, a research scientist 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 in mice. The study was led by first author Claire Gao, Ph.D., a postdoctoral fellow at the NIH National Institute of General Medical Sciences (NIGMS).
By blocking or removing specific signaling molecules within neurons, scientists were able to identify which cellular pathways play the biggest role in weight loss effects.
Their experiments showed that semaglutide’s effects depended largely on increases in cyclic adenosine monophosphate (cAMP) levels in the posterior cortex, a part of the brain involved in appetite regulation. However, the response was not the same for all neurons.
“This was not an all-or-nothing phenomenon; we observed a continuous change in cAMP responses between cells,” said co-author Michael Krashes, Ph.D., a senior investigator at NIDDK.
Why some GLP-1 effects fade over time
The researchers found that some neurons maintained high cAMP levels for long periods of time while semaglutide was present. Other neurons showed only a transient increase. According to the authors, some cells may reduce their response by internalizing or destroying GLP-1 receptors.
The team also tested whether these signals could be extended. By using the drug roflumilast, which blocks PDE4, an enzyme that breaks down cAMP, they were able to shift more neurons toward longer-lasting responses.
This discovery increases the likelihood that future GLP-1 treatments will remain effective for longer periods of time, potentially reducing the frequency with which patients need injections. Scientists also believe that this type of cAMP modulation may ultimately help overcome the weight loss plateau commonly reported with GLP-1 drugs. The researchers cautioned that more studies are needed to confirm this possibility.
Next steps in GLP-1 research
One of the limitations of this study was that the researchers could only observe intracellular signaling in brain tissue for a few hours at a time. The research team hopes to use new techniques in future studies to track how GLP-1 drugs affect neurons over days or weeks.
The findings provide a deeper look into the brain chemistry behind GLP-1 drugs and may help develop more effective weight loss treatments in the future.
