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 beta-cell function was previously elucidated using a pregnant mouse model. During pregnancy, 5-HT increases beta-cell proliferation and glucose-stimulated insulin secretion (GSIS) through the G alpha(q)-coupled 5-HT2b receptor (Htr2b) and the 5-HT3 receptor (Htr3), a ligand-gated cation channel, respectively. However, the role of 5-HT in beta-cell function in an insulin-resistant state has yet to be elucidated. Here, we characterized the metabolic phenotypes of beta-cell-specific Htr2b(-/-) (Htr2b beta KO), Htr3a(-/-) (Htr3a knock-out [KO]), and beta-cell-specific tryptophan hydroxylase 1 (Tph1)(-/-) (Tph1 beta KO) mice on a high-fat diet (HFD). Htr2b beta KO, Htr3a KO, and Tph1 beta KO mice 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 Tph1 beta KO mice developed glucose intolerance, but Htr2b beta KO mice 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 beta KO mice, and 5-HT treatment improved insulin secretion from Tph1 beta KO islets but not from Htr3a KO islets. Tph1 and Htr3a gene expression in pancreatic islets was not affected by an HFD, and immunostaining could not detect 5-HT in pancreatic is lets from mice fed an HFD. Taken together, these results demonstrate that basal 5-HT levels in beta-cells play a role in GSIS through Htr3, which becomes more evident in a diet-induced insulin-resistant state.