Glucagon-like peptide-2 (GLP-2) is known to exert some of its biological effects via 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 VEGFR3 as an intermediate in the signaling cascade. Utilizing a rat lymph fistula model, 5 hours after an intraduodenal (i.d.) lipid bolus, the following intraperitoneal (i.p.) administrations were applied in two different sets of experiments: Experiment 1: 1) Placebo, 2) GLP-2, 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 mins (Experiment 1) or 90 mins (Experiment 2) after administration. In another set of animals, GLP-2 or serotonin were administered i.p 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 utilized 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 abolished serotonin-induced lymph flow and TG output.
Tian et al. (2025) studied this question.