Serotonin regulates maternal-perinatal pancreatic beta cell mass and function

Abstract

1) during lactation and 2) perinatal period. During lactation, circulating prolactin activates PRLR-STAT5-TPH1 cascade to produce 5-HT in β cells. 5-HT stimulates β cell proliferation through HTR2B in an autocrine/paracrine manner, while intracellular 5-HT acts as an antioxidant to mitigate the intracellular oxidative stress in β cells. Taken together, 5-HT mediates the long-term beneficial effects of lactation on female metabolic health by increasing β cell proliferation and reducing oxidative stress in β cells. During perinatal period, newly developed β cells produce 5-HT shortly after a surge of growth hormone (GH), and 5-HT function in an autocrine/paracrine manner to drive β cell proliferation. In β cell-specific Tph1 KO mice, β cell proliferation was reduced to one-fourth during perinatal period. Furthermore, adult Tph1 βKO mice exhibited impaired glucose tolerance with decreased β cell mass and impaired insulin secretion. Disruption of Htr2b in β cells resulted in decreased β cell proliferation and mass indicating that HTR2B is the downstream of 5-HT in β cell proliferation. GH induced β cell 5-HT production during perinatal period comprising the GHR-STAT5-TPH1-5-HT-HTR2B axis in the perinatal β cell proliferation. Taken together, 5-HT plays a critical role in the glucose homeostasis and determination of β cell mass and by regulating β cell proliferation during lactation and perinatal period and exerting antioxidant activity by scavenging oxidative stress.

Impaired pancreatic β cell function is a predisposing factor in the development of type 2 diabetes. Various causes for β cell failure include ER stress glucolipotoxicity, mitochondrial dysfunction, etc. Recent advances in genetics discovered a number of genetic alterations that increases the risk of type 2 diabetes. However, ways to prevent β cells from failure are yet to be discovered. Serotonin (5-hydroxytryptamine, 5-HT), previously known as a neurotransmitter, is produced in different peripheral tissues to exert various functions. In this thesis, I focused on two physiological periods that pancreatic β cells produce 5-HT