Functional role of serotonin in insulin secretion in a diet-induced insulin-resistant state

The physiological role of serotonin, or 5-hydroxytryptamine (5-HT), in pancreatic-cell function was previously elucidated using a pregnant mouse model. During pregnancy, 5-HT increases-cell proliferation and glucose-stimulated insulin secretion (GSIS) through the Gq-coupled 5-HT2b receptor (Htr2b) and the 5-HT3 receptor (Htr3), a ligand-gated cation channel, respectively. However, the role of 5-HT in-cell function in an insulin-resistant state has yet to be elucidated. Here, we characterized the metabolic phenotypes of-cell-specific Htr2b/ (Htr2b KO), Htr3a/ (Htr3a knock-out [KO]), and-cell-specific tryptophan hydroxylase 1 (Tph1) / (Tph1KO) mice on a high-fat diet (HFD). Htr2bKO, Htr3a KO, and Tph1KOmice exhibited normal glucose tolerance on a standard chow diet. After 6 weeks on an HFD, beginning at 4 weeks of age, both Htr3a KO and Tph1KOmice developed glucose intolerance, but Htr2bKOmice remained normoglycemic. Pancreas perfusion assays revealed defective first-phase insulin secretion in Htr3a KO mice. GSIS was impaired in islets isolated from HFD-fed Htr3a KO and Tph1 KO mice, and 5-HT treatment improved insulin secretion from Tph1KOislets but not from Htr3aKOislets. Tph1 and Htr3a gene expression in pancreatic islets was not affected by an HFD, and immunostaining could not detect 5-HT in pancreatic isletsfrommice fedanHFD.Takentogether, these results demonstrate that basal 5-HT levels in-cells play a role in GSIS through Htr3, which becomes more evident in a diet-induced insulin-resistant state..