NIH researchers discover how weight-loss drugs alter brain cells

A team of researchers at the National Institutes of Health (NIH) have unveiled new details about the events GLP-1 receptor agonists trigger within neurons, which have been largely unexplored until now. A study in mice identified key intracellular signaling processes that are tied to the weight-loss effects of the GLP-1 drug semaglutide. The findings improve our understanding of how increasingly prevalent GLP-1s may influence human behavior and identify new opportunities to potentially enhance treatment.

The weight-loss benefits of GLP-1s are well documented and scientists generally know the brain regions associated with these effects. However, several questions remain, such as why responses to medication differ between patients and why the effects for most eventually plateau.

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."

Andrew Lutas, Ph.D., co-corresponding author, investigator at NIH's National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Experiments led by first author Claire Gao, Ph.D., a postdoctoral fellow at NIH's National Institute of General Medical Sciences (NIGMS), utilized a fluorescence imaging technique to explore semaglutide-induced intracellular activity in living brain tissue from mice. By selectively inhibiting or removing different intracellular signaling molecules, the researchers were able to identify which ones were most important for weight loss

Researchers found that the drug's weight-loss effects hinged on increased levels of the signaling molecule cyclic adenosine monophosphate, or cAMP, in the area postrema - a brain region containing circuits related to appetite. However, these increases varied from neuron to 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.

Some cells sustained their elevated cAMP levels in the presence of semaglutide. Meanwhile, other neurons only experienced temporary increases, possibly because they internalized or degraded their GLP-1 receptors, the authors explained. By inhibiting the naturally occurring enzyme PDE4, which degrades cAMP, with the drug roflumilast they showed that they could skew neurons toward a sustained response.

The finding suggests that the effects of GLP-1s could be extended, potentially reducing how often these drugs must be administered. Eventually, cAMP modulation may be a way to break past plateaus experienced by many patients. Finding out will require much more work, the authors noted.

The methods only permitted researchers to examine intracellular signaling in brain tissue over a matter of hours. In the future, the researchers aim to apply new techniques to study the intracellular effects of GLP-1s over days and weeks.