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

Abstract

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

Distinct Pattern of NPY in Gastro–Entero–Pancreatic System of Goat Kids Fed with a New Standardized Red Orange and Lemon Extract (RLE)

“…At intestinal levels, NPY acts in autocrine or paracrine manner to regulate all aspects of nutrient homeostasis including satiety, mechanical and chemical digestion, nutrient absorption, storage and utilization [49]. In addition, we observed NPY immunoreactivity in glucagon cells of pancreatic islets, further confirmed by immunofluorescence experiments which excluded co-presence of NPY with 5-HT, known to be marker of insulin cells [50,51]. 5-HT is synthesized by β-cells and promotes their functions [52], regulating insulin secretion as local autocrine/paracrine signal [53] and inhibiting glucan secretion in paracrine manner [50].…”

Serotonergic regulation of energy metabolism in peripheral tissues

“…During the perinatal period, disruption of Tph1 in β-cells resulted in their loss of 5-HT production, reducing perinatal β-cell proliferation and β-cell mass by more than 50%. This reduction in β-cell mass impaired glucose tolerance in adulthood and increased susceptibility to diabetes in response to metabolic stress (Moon et al 2020b). Furthermore, β-cell-specific Htr2b knock-out mice phenocopied β-cell-specific Tph1 knock-out mice, suggesting that HTR2B acts downstream of 5-HT in regulating perinatal β-cell proliferation.…”

Paracrine regulation of insulin secretion

“…In human islets, 5-HT serves a paracrine role by inhibiting glucagon release from alpha cells [39,40]. In mice, 5-HT production is normally low, but a notable increase in the local production of 5-HT by mouse beta cells is responsible for the robust increase in beta cell mass during pregnancy [41] and drives the perinatal expansion of beta cell mass that determines adult beta cell mass [42]. GABA is synthesised by GAD expressed by beta cells (in fact, GAD is an autoantigen in type 1 diabetes).…”