Differential role of GPR142 in tryptophan-mediated enhancement of insulin secretion in obese and lean mice

Yoko Ueda,Asako Doi,Hiroyuki Ariyasu,Shuhei Morita,Mika Bando,Hiroshi Iwakura,Takashi Akamizu,Hidefumi Inaba,Claudia Miele

doi:10.1371/journal.pone.0198762

Abstract

Tryptophan is reportedly the most potent agonist for GPR142. Glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells are enhanced by GPR142-mediated signal. It is not clear, however, if GPR142-mediated signals is solely attributable to GSIS enhancement after tryptophan load in various pathophysiological settings. This study aims to reveal the significance of GPR142 signaling in tryptophan-mediated GSIS enhancement in normal and obese mice. Tryptophan significantly improved glucose tolerance in both lean and DIO mice, but the extent of improvement was bigger in DIO mice with augmented glucose-stimulated insulin secretion (GSIS) enhancement. The same results were obtained in ob/ob mice. GPR142 deletion almost completely blocked tryptophan actions in lean mice, suggesting that GPR142 signaling was solely responsible for the GSIS enhancement. In obese GPR142KO mice, however, a significant amount of tryptophan effects were still observed. Calcium-sensing receptors (CaSR) are also known to recognize tryptophan as ligand. Expression levels of CaSR were significantly elevated in the pancreas of DIO mice, and CaSR antagonist further blocked tryptophan’s actions in DIO mice with GPR142 deletion. Although GPR142 signaling had a major role in tryptophan recognition for the enhancement of GSIS in lean mice, other pathways including CaSR signaling also had a significant role in obese mice, which seemed to contribute to the augmented enhancement of GSIS by tryptophan in these animals.

Highlights

The emerging role of nutrient-sensing receptors in glucose metabolisms and body energy homeostasis has gained the attention of many researchers [1]
Comprehensive profiling of G-protein coupled receptors (GPCRs) in MGN3-1 revealed that recently deorphanaized aromatic amino acid receptor, GPR142 [9] is highly expressed in the cells [8]
GPR142 expression levels in the stomach (G) and pancreas (H) of mice fed with standard diet (SD) and 60% high fat diet (HFD) for eighteen weeks. n = 6, ÃÃ: p

Summary

Introduction

The emerging role of nutrient-sensing receptors in glucose metabolisms and body energy homeostasis has gained the attention of many researchers [1]. Endocrine cells in the gastrointestinal tract sense the nutrients by the nutrient-sensing receptors, releasing various peptide hormones, including ghrelin, cholecystokinin, peptide YY, glucagon-like peptide-1, and gastric inhibitory peptide, to regulate food intake or insulin secretion. GPR120, a long-chain fatty acid receptor, is expressed in the gastric X/A-like cells and intestinal L cells to regulate the secretion of both ghrelin [2, 3] and GLP-1 [4]. GPR142 role in GSIS-enhancement by tryptophan in obese mice chain fatty acid receptor GPR40, are expressed in pancreatic beta cells controlling insulin secretion [5], and are considered to be potential drug-targets for treatment of diabetes [6]. We previously found that L-tryptophan (L-Try) strongly stimulates ghrelin secretion from both the ghrelin-producing cell line, MGN3-1 [7] and primary cultured stomach epithelial cells [8]. Knockdown of GPR142 by siRNA significantly attenuated L-Tryinduced ghrelin secretion, suggesting that GPR142 plays a key role in the L-Try-mediated ghrelin secretion [8]

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