Researchers at NIH's National Institute of Diabetes and Digestive and Kidney Diseases have made a significant breakthrough in understanding how GLP-1 receptor agonists like semaglutide induce weight loss. By utilizing a fluorescence imaging technique to explore semaglutide-induced intracellular activity in living brain tissue from mice, the team found that the drug's weight-loss effects hinge on increased levels of the signaling molecule cyclic adenosine monophosphate, or cAMP, in the area postrema — a brain region containing circuits related to appetite.
The Role of cAMP in Weight Loss The study, led by first author Claire Gao, Ph.D., a postdoctoral fellow at NIH's National Institute of General Medical Sciences, revealed that cAMP responses across cells varied on a continuum, with some cells sustaining their elevated cAMP levels in the presence of semaglutide and others experiencing temporary increases.
Potential for Enhanced Treatment By inhibiting the naturally occurring enzyme PDE4, which degrades cAMP, with the drug roflumilast, the researchers showed that they could skew neurons toward a sustained response, potentially extending the effects of GLP-1s and reducing the frequency of administration. This finding suggests that cAMP modulation may be a way to break past plateaus experienced by many patients, although further research is needed to confirm this. The discovery of the intracellular signaling processes that contribute to the weight-loss effects of GLP-1 receptor agonists could lead to more effective treatments for obesity and related diseases, and the NIH team aims to apply new techniques to study the intracellular effects of GLP-1s over days and weeks in future research.
Source: NIH researchers identify avenue for enhanced GLP-1-induced weight loss
Domain: nih.gov
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