A team of researchers at the National Institutes of Health (NIH) has uncovered new details about the events that GLP-1 receptor agonists trigger in neurons, which were previously largely unknown. Studies in mice have identified key intracellular signaling processes associated with the weight-loss effects of the GLP-1 drug semaglutide. This discovery advances our understanding of how the increasingly prevalent GLP-1 influences human behavior and identifies new opportunities that may enhance treatments.
The weight loss effects of GLP-1 are well documented, and scientists generally know the brain regions associated with these effects. But several questions remain, including why patients respond differently to the drugs and why the effects eventually plateau for most patients.
Little is known about the details of what happens within the neurons targeted by these drugs. By taking a closer look at these mechanisms, we are beginning to answer some of these questions. ”
Dr. Andrew Lutas, co-corresponding author, researcher at the NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
The experiments, led by first author Claire Gao, Ph.D., a postdoctoral fellow at the NIH National Institute of General Medical Sciences (NIGMS), used fluorescence imaging techniques to examine semaglutide-induced intracellular activity in living mouse brain tissue. By selectively inhibiting or removing different intracellular signaling molecules, researchers were able to identify which are most important for weight loss.
The researchers found that the drug’s weight-loss effects depended on increased levels of the signaling molecule cyclic adenosine monophosphate (cAMP) in the posterior cortex, a brain region that contains circuits related to appetite. However, these increases varied from neuron to neuron.
“This was not an all-or-nothing phenomenon. We observed that cAMP responses between cells varied continuously.” “This is an important step forward in our research,” said co-corresponding author Michael Krashes, Ph.D., senior research scientist at NIDDK.
Some cells maintained elevated cAMP levels in the presence of semaglutide. Meanwhile, other neurons experienced only a temporary increase, likely because they had internalized or degraded GLP-1 receptors, the authors explained. They showed that by inhibiting the natural enzyme PDE4, which breaks down cAMP, with the drug roflumilast, neurons could be biased towards a sustained response.
This finding suggests that the effects of GLP-1 may be prolonged and the frequency of administration of these drugs may be reduced. Ultimately, cAMP modulation may be a way to break the plateau that many patients experience. The authors note that more work is needed to figure this out.
This method only allowed researchers to examine intracellular signaling in brain tissue over a period of several hours. In the future, the researchers aim to apply new techniques to study the intracellular effects of GLP-1 over days or weeks.
sauce:
National Institutes of Health (NIH)
Reference magazines:
Gao, C. others. (2026) Semaglutide promotes weight loss via a cAMP-dependent mechanism in hindbrain neurons expressing GLP1R-1. natural metabolism. DOI: 10.1038/s42255-026-01534-8. https://www.nature.com/articles/s42255-026-01534-8
