Mechano-Sensing Piezo1 Channels Regulate Glucagon-Like Peptide-1 Production in Intestinal L Cells

Core Concepts

Piezo1 channels expressed in intestinal L cells mediate mechanical stimuli from the intestinal lumen and trigger the synthesis and secretion of glucagon-like peptide-1 (GLP-1) through the CaMKKβ/CaMKIV-mTORC1 signaling pathway, thereby regulating glucose homeostasis.

Abstract

The study investigated the role of the mechanosensitive ion channel Piezo1 in the regulation of GLP-1 production by intestinal L cells. Key findings:

Piezo1 is expressed in intestinal L cells and its expression level correlates with blood glucose and GLP-1 levels. Mice with L cell-specific loss of Piezo1 (IntL-Piezo1-/-) exhibited impaired glucose tolerance, increased body weight, reduced GLP-1 production, and decreased CaMKKβ/CaMKIV-mTORC1 signaling.

Activation of intestinal Piezo1 by its agonist Yoda1 or intestinal bead implantation increased GLP-1 synthesis and secretion, thus alleviating glucose intolerance in diet-induced diabetic mice.

Overexpression of Piezo1, Yoda1 treatment, or mechanical stretching stimulated GLP-1 production and CaMKKβ/CaMKIV-mTORC1 signaling in primary cultured mouse L cells and STC-1 cells, which could be abolished by knockdown or blockage of Piezo1.

The CaMKKβ/CaMKIV-mTORC1 signaling pathway mediates the effects of Piezo1 on GLP-1 production. Inhibition of CaMKKβ or mTORC1 suppressed the Piezo1-induced increase in GLP-1 synthesis and secretion.

These findings suggest a previously undiscovered mechano-regulation of GLP-1 production in intestinal L cells, which may provide new insights for the treatment of diabetes.

Stats

Mice with L cell-specific loss of Piezo1 (IntL-Piezo1-/-) exhibited impaired glucose tolerance and reduced GLP-1 production compared to control mice.
Activation of intestinal Piezo1 by Yoda1 or intestinal bead implantation increased GLP-1 synthesis and secretion, and alleviated glucose intolerance in diet-induced diabetic mice.
Overexpression of Piezo1, Yoda1 treatment, or mechanical stretching stimulated GLP-1 production and CaMKKβ/CaMKIV-mTORC1 signaling in primary cultured mouse L cells and STC-1 cells.
Inhibition of CaMKKβ or mTORC1 suppressed the Piezo1-induced increase in GLP-1 synthesis and secretion.

Quotes

"Piezo1 channels expressed in intestinal L cells mediate mechanical stimuli from the intestinal lumen and trigger the synthesis and secretion of glucagon-like peptide-1 (GLP-1) through the CaMKKβ/CaMKIV-mTORC1 signaling pathway, thereby regulating glucose homeostasis."
"These findings suggest a previously undiscovered mechano-regulation of GLP-1 production in intestinal L cells, which may provide new insights for the treatment of diabetes."

Key Insights Distilled From

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

by Huang,Y., Mo... at www.biorxiv.org 04-02-2024

https://www.biorxiv.org/content/10.1101/2024.04.01.587569v1

Deeper Inquiries

What other potential mechanisms or signaling pathways might be involved in the mechano-regulation of GLP-1 production by Piezo1 in intestinal L cells

The mechano-regulation of GLP-1 production by Piezo1 in intestinal L cells may involve several other potential mechanisms and signaling pathways. One possible mechanism is the involvement of the Hippo signaling pathway, which has been implicated in mechanotransduction processes in various cell types. Activation of Piezo1 by mechanical stimuli could potentially trigger downstream effectors of the Hippo pathway, leading to the regulation of gene expression related to GLP-1 production. Additionally, the Wnt signaling pathway, known for its role in cell proliferation and differentiation, could also play a role in mediating the mechano-regulation of GLP-1 synthesis by Piezo1. Activation of Piezo1 may influence Wnt signaling components, impacting the transcriptional regulation of genes involved in GLP-1 production. Furthermore, the MAPK/ERK pathway, a key signaling cascade involved in cellular responses to mechanical stimuli, could be another pathway through which Piezo1 regulates GLP-1 production. Activation of Piezo1 may lead to the activation of MAPK/ERK signaling, ultimately influencing the synthesis and secretion of GLP-1 in intestinal L cells.

How might the findings from this study be translated into the development of new therapeutic strategies for the treatment of type 2 diabetes and other metabolic disorders

The findings from this study hold significant promise for the development of new therapeutic strategies for the treatment of type 2 diabetes and other metabolic disorders. Understanding the mechano-sensing function of Piezo1 in the gastrointestinal system provides a novel target for drug development aimed at modulating GLP-1 production. By targeting Piezo1 or its downstream signaling pathways, such as CaMKKβ/CaMKIV-mTOR, it may be possible to enhance GLP-1 secretion and improve glucose homeostasis in diabetic individuals. Pharmacological agents that activate Piezo1 or enhance its mechano-sensing capabilities could be developed as potential treatments for diabetes. Additionally, the identification of Piezo1 as a key player in the mechano-regulation of GLP-1 production opens up avenues for personalized medicine approaches, where therapies targeting Piezo1 could be tailored to individual patients based on their specific mechanosensitivity profiles.

Given the role of Piezo1 in various physiological processes, what are the potential broader implications of understanding the mechano-sensing function of Piezo1 in the gastrointestinal system

The understanding of the mechano-sensing function of Piezo1 in the gastrointestinal system has broader implications beyond the regulation of GLP-1 production. Piezo1 is a widely expressed mechanosensitive ion channel involved in various physiological processes, including blood pressure regulation, bone homeostasis, and cardiac function. By elucidating the role of Piezo1 in the mechano-regulation of GLP-1 production, this study contributes to the broader understanding of how mechanical forces influence cellular functions in the gastrointestinal tract. The findings may have implications for other gastrointestinal hormones and signaling pathways that are sensitive to mechanical stimuli. Furthermore, the study of Piezo1 in the context of metabolic disorders like diabetes sheds light on the interconnectedness of mechanotransduction and metabolic regulation, highlighting the importance of considering mechanical cues in the development of therapeutic interventions for metabolic diseases.