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

Glucagon-like peptide 1 receptor (GLP1R) agonists, such as semaglutide, drive weight loss by binding to GLP1Rs-classically described as G_s-coupled G-protein-coupled receptors-in the brain; however, the intracellular signalling mechanisms underlying these effects remain poorly defined. Here, we find that semaglutide engages both G_s- and G_q-dependent signalling pathways in Glp1r-expressing neurons in the area postrema (AP^Glp1r), the primary site of semaglutide action in the brain, and differentially regulates neuronal activation across distinct neuronal clusters. Semaglutide also drives graded increases of the essential secondary messenger cyclic adenosine monophosphate (cAMP) in AP^Glp1r neurons through the G_s pathway. Inhibition of the cAMP-degrading enzyme phosphodiesterase 4 (PDE4) enhances and sustains these cAMP responses, and disruption of G_s or cAMP signalling in AP^Glp1r neurons abolishes semaglutide-induced weight loss and downstream brain-wide activation. Our systematic characterization of semaglutide's signalling mechanisms in the hindbrain reveals the intracellular signalling architecture through which semaglutide engages cAMP and calcium to regulate body weight, providing avenues for improving obesity therapeutics.