Serotonin Regulates Adult β-Cell Mass by Stimulating Perinatal β-Cell Proliferation

A sufficient beta-cell mass is crucial for preventing diabetes, and perinatal beta-cell proliferation is important in determining the adult beta-cell mass. However, it is not yet known how perinatal beta-cell proliferation is regulated. Here, we report that serotonin regulates beta-cell proliferation through serotonin receptor 2B (HTR2B) in an autocrine/paracrine manner during the perinatal period. In beta-cell-specific Tph1 knockout (Tph1 beta KO) mice, perinatal beta-cell proliferation was reduced along with the loss of serotonin production in beta-cells. Adult Tph1 beta KO mice exhibited glucose intolerance with decreased beta-cell mass. Disruption of Htr2b in beta-cells also resulted in decreased perinatal beta-cell proliferation and glucose intolerance in adulthood. Growth hormone (GH) was found to induce serotonin production in beta-cells through activation of STAT5 during the perinatal period. Thus, our results indicate that GH-GH receptor-STAT5-serotonin-HTR2B signaling plays a critical role in determining the beta-cell mass by regulating perinatal beta-cell proliferation, and defects in this pathway affect metabolic phenotypes in adults.