Abstract
Lorcaserin is a serotonergic agonist specific to the 5-hydroxytryptamine 2c receptor (5-HT2CR) that is FDA approved for the long-term management of obesity with or without at least one weight-related comorbidity. Lorcaserin can restrain patients’ appetite and improve insulin sensitivity and hyperinsulinemia mainly through activating 5-HT2CR in the hypothalamus. It is known that the mCPP, a kind of 5-HT2CR agonist, decreases plasma insulin concentration in mice and previous research in our laboratory found that mCPP inhibited glucose-stimulated insulin secretion (GSIS) by activating 5-HT2CR on the β cells. However, the effect of lorcaserin on GSIS of pancreatic β cell has not been studied so far. The present study found that 5-HT2CR was expressed in both mouse pancreatic β cells and β-cell–derived MIN6 cells. Dose-dependent activation of 5-HT2CR by lorcaserin suppressed GSIS and SB242084 or knockdown of 5-HT2CR abolished lorcaserin’s effect in vitro. Additionally, lorcaserin also suppressed GSIS in high-fat diet (HFD)-fed mice in dose-dependent manner. Lorcaserin did not change insulin synthesis ATP content, but lorcaserin decrease cytosolic free calcium level [(Ca2+)i] in MIN6 cells stimulated with glucose and also inhibit insulin secretion and (Ca2+)i in MIN6 treated with potassium chloride. Furthermore, stimulation with the L-type channel agonist, Bay K8644 did not restore GSIS in MIN6 exposed to lorcaserin. Lorcaserin inhibits the cAMP generation of MIN6 cells and pretreatment with the Gα i/o inhibitor pertussis toxin (PTX), abolished lorcaserin-induced suppression of GSIS in β cells, while membrane-permeable cAMP analogue db-cAMP had same effect as PTX. These date indicated lorcaserin coupled to PTX-sensitive Gα i/o proteins in β cells reduced intracellular cAMP level and Ca2+ influx, thereby causing GSIS dysfunction of β cell. These results highlight a novel signaling mechanism of lorcaserin and provide valuable insights into the further investigation of 5-HT2CR functions in β-cell biology and it also provides guidance for the clinical application of lorcaserin.
Highlights
The prevalence of obesity has become a major global health problem in both adults and adolescents (Eva et al, 2018)
Previous research in our laboratory found that meta-chlorophenylpiperazine, a 5-hydroxytryptamine 2C receptor (5-HT2CR) agonist, could inhibit glucose-stimulated insulin secretion (GSIS) in isolated mouse islets and MIN6 cells and that a 5-HT2CR antagonist SB242084 could reverse the inhibitory effects on the secretion of insulin produced by mCPP (Zhang et al, 2013)
Serotonin (5-HT) is a neurotransmitter, which can colocalize with insulin in secretory granules and cosecrete with insulin upon glucose-stimulation (Ohta et al, 2011; Kim et al, 2015). 5-HT produced contradictory results on the secretion of insulin; an inhibition (Lernmark, 1971; Zawalich et al, 2004) or a stimulation (Peschke et al, 1997) of GSIS has been observed in rodent islet. 5-HT receptors include seven distinct families and virtually all 5-HT receptors are G protein-coupled with the exception of 5-HT3 receptors (Wyler et al, 2017)
Summary
The prevalence of obesity has become a major global health problem in both adults and adolescents (Eva et al, 2018). 5-HT is synthesized and co-secreted along with insulin in pancreatic β cells, potentially acting as a local autocrine/paracrine signal on insulin secretion (Ohta et al, 2011) and Interferes with the synthesis of 5-HT synthesis in beta cells impairs insulin secretion (Kim et al, 2015) All these suggested that the 5-HT2CR may play a direct role in regulating islet β cells function. In 2020, FDA sent a drug safety communication (DSC) reporting that more cancer cases were diagnosed after lorcaserin treatment (n 462; 7.7%) compared to those in placebo group (n 423; 7.1%) in a randomized, doubleblind, placebo controlled clinical trial (FDA, 2020), which differs from the peer-reviewed publication claiming that cancer numbers is 215 (3.59%) and 210 (3.50%) in patients taking lorcaserin and in placebo, respectively (Bohula et al, 2018b). We investigated the effect of lorcaserin on GSIS of pancreatic β cells in vitro and in vivo, and explore the possible underlying molecular mechanism
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