cAMP signaling in GLP1R-expressing Area Postrema cells is necessary for semaglutide-induced neuronal activation

Authors

• IC Geneve
• C Gao
• A Lutas

Abstract

Semaglutide, a glucagon-like peptide 1 receptor (GLP1R) agonist, is an FDA-approved treatment for obesity. GLP1Rs are G-protein coupled receptors that couple the stimulatory Gɑs protein, leading to the production of the secondary messenger cyclic adenosine monophosphate (cAMP). While it is known that semaglutide acts on GLP1Rs in the brain, whether Gɑs signaling and cAMP activation mediates semaglutide-induced neuronal activation remains unclear. To determine whether semaglutide signals through the Gαs protein in the brain, we quantified semaglutide-induced Fos activation–a proxy for neuronal activity–in conditional knockout mice lacking the Gnas gene, which encodes for the Gαs protein, in all Glp1r-expressing cells (Glp1r-ires-cre; Gnasfl/fl) or controls (Gnasfl/fl). Mice lacking Gαs signaling in Glp1r-expressing cells lacked Fos activation to semaglutide injection compared to control mice, particularly in area postrema (AP).

Previous studies have shown that the AP is enriched in GLP1Rs and fluorescently tagged semaglutide localizes to the AP, suggesting that this region may be a primary target for the effects of semaglutide on the brain. To test the necessity of cAMP signaling in the AP, we expressed a constitutively active form of phosphodiesterase (PDE4D3-Cat), an enzyme responsible for cAMP degradation, into GLP1R-expressing neurons in the AP and quantified semaglutide mediated Fos activation in comparison to control mice. Our findings indicate that cAMP signaling, specifically in APGLP1R cells, is necessary for semaglutide-induced Fos activation in the AP and downstream regions, such as the elPBN.

Scientific Focus Area: Neuroscience

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