Here, we focus on identifying the effect of more nuanced changes in cholesterol content on exendin-4-mediated GLP-1R function in primary islets and in vivo , followed by mapping of cholesterol binding sites for both apo-state and active receptor structures using coarse-grained molecular dynamics (cgMD) simulations tailored to identify lipid-receptor interactions, and functional validation of a prominent site for its effects on cholesterol binding, plasma membrane behaviours and exendin-4-mediated GLP-1R function in beta cells and primary islets
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By applying a reverse translational approach that evaluates compounds with emerging clinical efficacy, we demonstrated that semaglutide, tirzepatide, and retatrutide blunt alcohol interoceptive/subjective effects, potentially clarifying a clinically meaningful mechanism
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