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机械调节肠道 L 细胞中 Piezo1 对 GLP-1 的产生。

Mechano-regulation of GLP-1 production by Piezo1 in intestinal L cells.

机构信息

Department of Physiology, School of Medicine, Jinan University, Guangzhou, China.

Department of Pathology, School of Basic Medicine, Guangzhou Medical University, Guangdong, China.

出版信息

Elife. 2024 Nov 7;13:RP97854. doi: 10.7554/eLife.97854.

DOI:10.7554/eLife.97854
PMID:39509292
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11542922/
Abstract

Glucagon-like peptide 1 (GLP-1) is a gut-derived hormone secreted by intestinal L cells and vital for postprandial glycemic control. As open-type enteroendocrine cells, whether L cells can sense mechanical stimuli caused by chyme and thus regulate GLP-1 synthesis and secretion is unexplored. Molecular biology techniques revealed the expression of Piezo1 in intestinal L cells. Its level varied in different energy status and correlates with blood glucose and GLP-1 levels. Mice with L cell-specific loss of Piezo1 ( IntL-CKO) exhibited impaired glucose tolerance, increased body weight, reduced GLP-1 production and decreased CaMKKβ/CaMKIV-mTORC1 signaling pathway under normal chow diet or high-fat diet. Activation of the intestinal Piezo1 by its agonist Yoda1 or intestinal bead implantation increased the synthesis and secretion of GLP-1, thus alleviated glucose intolerance in diet-induced-diabetic mice. Overexpression of Piezo1, Yoda1 treatment or stretching stimulated GLP-1 production and CaMKKβ/CaMKIV-mTORC1 signaling pathway, which could be abolished by knockdown or blockage of Piezo1 in primary cultured mouse L cells and STC-1 cells. These experimental results suggest a previously unknown regulatory mechanism for GLP-1 production in L cells, which could offer new insights into diabetes treatments.

摘要

胰高血糖素样肽 1（GLP-1）是一种由肠道 L 细胞分泌的肠源激素，对餐后血糖控制至关重要。作为开放型肠内分泌细胞，L 细胞能否感知食糜引起的机械刺激，从而调节 GLP-1 的合成和分泌尚不清楚。分子生物学技术揭示了 Piezo1 在肠道 L 细胞中的表达。其水平在不同的能量状态下变化，并与血糖和 GLP-1 水平相关。在正常饲料或高脂肪饮食下，L 细胞特异性缺失 Piezo1（IntL-CKO）的小鼠表现出葡萄糖耐量受损、体重增加、GLP-1 产生减少和 CaMKKβ/CaMKIV-mTORC1 信号通路减少。其激动剂 Yoda1 或肠道珠植入激活肠道 Piezo1 可增加 GLP-1 的合成和分泌，从而缓解饮食诱导的糖尿病小鼠的葡萄糖不耐受。Piezo1 的过表达、Yoda1 处理或拉伸刺激 GLP-1 的产生和 CaMKKβ/CaMKIV-mTORC1 信号通路，而在原代培养的小鼠 L 细胞和 STC-1 细胞中敲低或阻断 Piezo1 可消除这些作用。这些实验结果提示了 L 细胞中 GLP-1 产生的一个以前未知的调节机制，可为糖尿病治疗提供新的思路。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba67/11542922/cbb8abfa393a/elife-97854-sa4-fig1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba67/11542922/cbb8abfa393a/elife-97854-sa4-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba67/11542922/92372b63f1b7/elife-97854-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba67/11542922/095cbb087f7b/elife-97854-fig1-figsupp1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba67/11542922/52aeba4b6ff9/elife-97854-fig1-figsupp7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba67/11542922/c5df1e61408a/elife-97854-fig1-figsupp8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba67/11542922/5307b98adb3c/elife-97854-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba67/11542922/cd1592d8a35d/elife-97854-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba67/11542922/ccaebd279ed7/elife-97854-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba67/11542922/7762c1fe75f1/elife-97854-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba67/11542922/7af23222c196/elife-97854-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba67/11542922/c91d443c9de4/elife-97854-fig5.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba67/11542922/a8c253e0a03c/elife-97854-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba67/11542922/cbb8abfa393a/elife-97854-sa4-fig1.jpg

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