Serotonin, a downstream effector of GLP-2, enhances lacteal contractility and lymph flow

Glucagon-like peptide-2 (GLP-2) is known to exert some of its biological effects through the release of neurotransmitters, and in view of the absolute requirement for the enteric nervous system (ENS) demonstrated in our recent GLP-2-induced lipid mobilization studies, we aimed to identify the neurotransmitter that mediates GLP-2's effect on intestinal lipid mobilization. We also examined the role of vascular endothelial growth factor receptor 3 (VEGFR3) as an intermediate in the signaling cascade. Using a rat lymph fistula model, 5 h after an intraduodenal (id) lipid bolus, the following intraperitoneal (ip) administrations were applied in two different sets of experiments: Experiment 1: 1) placebo, 2) GLP-2, and 3) GLP-2 + ketanserin (serotonin receptor antagonist). Experiment 2: 1) placebo, 2) serotonin, 3) serotonin + MAZ-51 (a VEGFR3 inhibitor), 4) serotonin + SAR131675 (a second VEGFR3 inhibitor). Lymph flow and triglyceride (TG) output were assessed for 60 min (experiment 1) or 90 min (experiment 2) after administration. In another set of animals, GLP-2 or serotonin was administered intraperitoneally, and blood samples were collected to quantify plasma serotonin concentration. Intravital imaging of a prospero-related homeobox 1-enhanced green fluorescent protein rat model was used to assess lacteal contractility after placebo or serotonin administration. We demonstrated that single-dose GLP-2 administration acutely increased serotonin concentration in plasma, serotonin enhanced lymph flow, lymph TG output, and lacteal contractility. Antagonism of the serotonin receptor decreases GLP-2-enhanced mesenteric lymph flow and TG output, and inhibition of VEGFR3 abolishes serotonin-induced lymph flow and TG outputNEW & NOTEWORTHY Our data suggests that the neurotransmitter serotonin mediates glucagon-like peptide-2 (GLP-2)'s effect on intestinal lipid mobilization by enhancing lymph flow and lacteal contractility, and vascular endothelial growth factor receptor 3 (VEGFR3) is one of the downstream targets of serotonin involved in this cascade.