Semaglutide drives weight loss through cAMP-dependent mechanisms in GLP1R-expressing hindbrain neurons

Glucagon-like peptide 1 receptor (GLP1R) agonists like semaglutide drive weight loss through the brain, but insights into their intracellular signaling mechanisms are lacking. Although canonically GLP1Rs signal through the stimulatory alpha Gs protein, we find that semaglutide utilizes both Gs- and Gq-signaling pathways in GLP1Rs in the area postrema (AP)—the primary site of semaglutide action in the brain—to differentially regulate neuronal activation across distinct neuronal clusters. Semaglutide also drives graded increases of the essential secondary messenger cyclic adenosine monophosphate (cAMP) in Glp1r-expressing AP neurons (AP ^Glp1r ) through Gs-dependent and -independent manners. Inhibition of the cAMP-degradation enzyme phosphodiesterase 4 (PDE4) can enhance and sustain these cAMP responses, whereas disruption of Gs or cAMP signaling in AP ^Glp1r neurons abolishes semaglutide-induced weight loss and downstream brain-wide activation. Our systematic characterization of semaglutide’s signaling mechanisms in the brain provides avenues for improving the performance of obesity therapeutics.