
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.


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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. Our study showed 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-Piezo1-/- ) exhibited impaired glucose tolerance, increased body weight, reduced GLP-1 production and decreased CaMKKβ/CaMKIV-mTORC1 signaling pathway under normal chow diet or high fed 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 findings suggest a previously undiscovered mechano-regulation of GLP-1 production in L cells, which may shed new light on the treatments of diabetes.

### Competing Interest Statement

The authors have declared no competing interest.

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

mechano-sensing-piezo1-channels-regulate-glucagon-like-peptide-1-production-in-intestinal-l-cells


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


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SLC35G1, a member of the solute carrier (SLC) 35 family, plays a key role in the basolateral membrane transport of citrate in the intestinal absorption process.


The intestinal absorption of essential nutrients, especially those not readily biosynthesized, is a critical physiological process for maintaining homeostasis. Numerous studies have indicated that intestinal absorption is mediated by various membrane transporters. Citrate, a crucial bioactive compound produced as an intermediate in the Krebs cycle, is absorbed in the small intestine through carrier-mediated systems because of its high hydrophilicity. While the luminal absorption of citrate is mediated by Na+-dicarboxylate cotransporter 1 (NaDC1), the mechanism governing the release of the transported citrate into the bloodstream remains unknown. Here, we explored the transporters responsible for intestinal citrate absorption at the basolateral membrane, focusing on highly expressed orphan transporters in the small intestine as candidates. Consequently, SLC35G1, originally identified as a partner of stromal interaction molecule 1, a cell surface transmembrane glycoprotein, was found to play a role in the intestinal absorption of citrate at the basolateral membrane. Furthermore, our results revealed that SLC35G1-mediated citrate transport was diminished by chloride ions at extracellular concentrations. This suggests that SLC35G1, to our best knowledge, is the first transporter identified to be extremely sensitive to chloride ions among those functioning on the basolateral membrane of intestinal epithelial cells. This study provides valuable insights into the intestinal absorption of citrate and significantly contributes to elucidating the poorly understood molecular basis of the intestinal absorption system.

### Competing Interest Statement

The authors have declared no competing interest.

SLC35G1: A highly chloride-sensitive transporter responsible for the basolateral membrane transport in intestinal citrate absorption

slc35g1-a-highly-chloride-sensitive-transporter-crucial-for-basolateral-citrate-absorption-in-the-intestine


SLC35G1: A Highly Chloride-Sensitive Transporter Crucial for Basolateral Citrate Absorption in the Intestine



TRPV4 and its interaction with the calcium-activated chloride channel ANO1 play a crucial role in temperature-dependent perspiration in mice, with implications for understanding and treating human sweating disorders.


Reports indicate that an interaction between TRPV4 and anoctamin 1 could be widely involved in water efflux of exocrine glands, suggesting that the interaction could play a role in perspiration. In secretory cells of sweat glands present in mouse foot pads, TRPV4 clearly colocalized with cytokeratin 8, anoctamin 1 (ANO1) and aquaporin-5 (AQP5). Mouse sweat glands showed TRPV4-dependent cytosolic Ca2+ increases that was inhibited by menthol. Acetylcholine-stimulated sweating in foot pads was temperature-dependent in wild-type, but not in TRPV4-deficient mice, and was inhibited by menthol both in wild-type and TRPM8KO mice. The basal sweating without acetylcholine stimulation was inhibited by an ANO1 inhibitor. Sweating could be important for maintaining friction forces in mouse foot pads, and this possibility is supported by the finding that wild-type mice climbed up a slippery slope more easily than TRPV4-deleted mice. Furthermore, TRPV4 expression was significantly higher in controls and normohidrotic skin from patients with AIGA (acquired idiopathic generalized anhidrosis) compared to anhidrotic skin from patients with AIGA. Collectively, TRPV4 is likely involved in temperature-dependent perspiration via interactions with ANO1, and TRPV4 itself or the TRPV4/ANO 1 complex would be targets to develop agents that regulate perspiration.

### Competing Interest Statement

The authors have declared no competing interest.

Involvement of TRPV4 in temperature-dependent perspiration in mice

the-role-of-trpv4-in-temperature-dependent-perspiration-in-mice


The Role of TRPV4 in Temperature-Dependent Perspiration in Mice
