Drug Discovery BiologyMonash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
Drug Discovery BiologyMonash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
J Mol Endocrinol. 2018 Apr;60(3):213-224. doi: 10.1530/JME-17-0152.
Insulin-like peptide 5 (INSL5) is a newly discovered gut hormone expressed in colonic enteroendocrine L-cells but little is known about its biological function. Here, we show using RT-qPCR and hybridisation that mRNA is highly expressed in the mouse colonic mucosa, colocalised with proglucagon immunoreactivity. In comparison, mRNA for RXFP4 (the cognate receptor for INSL5) is expressed in various mouse tissues, including the intestinal tract. We show that the human enteroendocrine L-cell model NCI-H716 cell line, and goblet-like colorectal cell lines SW1463 and LS513 endogenously express Stimulation of NCI-H716 cells with INSL5 produced phosphorylation of ERK1/2 (Thr/Tyr), AKT (Thr and Ser) and S6RP (Ser) and inhibited cAMP production but did not stimulate Ca release. Acute INSL5 treatment had no effect on GLP-1 secretion mediated by carbachol or insulin, but modestly inhibited forskolin-stimulated GLP-1 secretion in NCI-H716 cells. However, chronic INSL5 pre-treatment (18 h) increased basal GLP-1 secretion and prevented the inhibitory effect of acute INSL5 administration. LS513 cells were found to be unresponsive to INSL5 despite expressing Another enteroendocrine L-cell model, mouse GLUTag cells did not express detectable levels of and were unresponsive to INSL5. This study provides novel insights into possible autocrine/paracrine roles of INSL5 in the intestinal tract.
胰岛素样肽 5（INSL5）是一种新发现的肠道激素，在结肠肠内分泌 L 细胞中表达，但对其生物学功能知之甚少。在这里，我们通过 RT-qPCR 和杂交显示，mRNA 在小鼠结肠黏膜中高度表达，与胰高血糖素原免疫反应性共定位。相比之下，mRNA 对于 RXFP4（INSL5 的同源受体）在各种小鼠组织中表达，包括肠道。我们表明，人肠内分泌 L 细胞模型 NCI-H716 细胞系以及杯状样结直肠细胞系 SW1463 和 LS513 内源性表达。刺激 NCI-H716 细胞的 INSL5 产生 ERK1/2（Thr/Tyr）、AKT（Thr 和 Ser）和 S6RP（Ser）的磷酸化，并抑制 cAMP 的产生，但不刺激 Ca 释放。急性 INSL5 处理对由 carbachol 或胰岛素介导的 GLP-1 分泌没有影响，但适度抑制 NCI-H716 细胞中 forskolin 刺激的 GLP-1 分泌。然而，慢性 INSL5 预处理（18 小时）增加了基础 GLP-1 分泌，并防止了急性 INSL5 给药的抑制作用。尽管 LS513 细胞表达，但对 INSL5 没有反应。另一种肠内分泌 L 细胞模型，小鼠 GLUTag 细胞未表达可检测水平的，对 INSL5 无反应。这项研究为 INSL5 在肠道中的可能自分泌/旁分泌作用提供了新的见解。
