NIH researchers have uncovered new details about how GLP-1 receptor agonists, like semaglutide, trigger events within neurons, identifying a potential avenue to enhance weight loss effects and improve treatment outcomes.
The study in mice, led by first author Claire Gao, Ph.D., and co-corresponding author Andrew Lutas, Ph.D., explored previously unexplored intracellular signaling processes tied to semaglutide's weight-loss benefits. This research aims to address why patient responses to GLP-1 medications vary and eventually plateau, a significant gap in current understanding. Dr. Lutas, an investigator at NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), said, "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."
Utilizing a fluorescence imaging technique on living brain tissue, the team found that the drug’s weight-loss effects hinged on increased levels of the signaling molecule cyclic adenosine monophosphate (cAMP) in the area postrema, a brain region containing circuits related to appetite. Co-corresponding author Michael Krashes, Ph.D., a senior investigator at NIDDK, noted, "It was not an all or nothing phenomenon. We observed that cAMP responses across cells varied on a continuum."
While some neurons sustained elevated cAMP levels, others experienced only temporary increases, possibly due to receptor internalization or degradation. By inhibiting the naturally occurring enzyme PDE4, which degrades cAMP, with the drug roflumilast, researchers demonstrated they could skew neurons toward a sustained response. This finding suggests that modulating cAMP could extend the effects of GLP-1s, potentially reducing administration frequency and helping patients overcome treatment plateaus, though further long-term research is required.