Abstract
Glucagon-like peptide-1 (GLP-1) receptor agonists are widely used to treat obesity and metabolic disease by suppressing food intake, yet their effects on fluid homeostasis remain poorly understood. Here we show that the GLP-1 analogue semaglutide robustly suppresses water intake in mice independently of its anorexigenic action, revealing an unexpected role for GLP-1 signaling in the control of drinking behavior. Semaglutide activates serotonergic neurons in the dorsal raphe nucleus (DRN), resulting in serotonin-mediated inhibition of 5-HT2C receptor–expressing neurons in the medial preoptic area (MPA). These MPA 5-HT2C neurons are activated immediately prior to drinking and encode an aversive motivational state; their chemogenetic or optogenetic activation induces excessive water intake, whereas their inhibition suppresses drinking. Conversely, genetic deletion of Htr2c in the MPA disinhibits this population, elevates basal water consumption, and abolishes semaglutide-induced suppression of drinking without affecting appetite regulation. Together, these findings identify a serotonin-modulated DRNàMPA circuit that selectively governs thirst and demonstrate that GLP-1 mediated suppression of drinking is mechanistically distinct from feeding suppression. This work uncovers a previously unrecognized dimension of GLP-1 signaling with implications for fluid balance regulation during anti-obesity therapy.