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 (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.

The zinc transporter Slc30a1 plays an essential role in maintaining cellular zinc homeostasis. Despite this, its functional role in macrophages remains largely unknown. Here, we examine the function of Slc30a1 in host defense using mice models infected with an attenuated stain of Salmonella enterica Typhimurium and primary macrophages infected with the attenuated Salmonella. Bulk transcriptome sequencing in primary macrophages identifies Slc30a1 as a candidate in response to Salmonella infection. Whole-mount immunofluorescence and confocal microscopy imaging of primary macrophage and spleen from Salmonella-infected Slc30a1^flag-EGFP mice demonstrate Slc30a1 expression is increased in infected macrophages with localization at the plasma membrane and in the cytosol. Lyz2-Cre-driven Slc30a1 conditional knockout mice (Slc30a1^fl/fl;Lyz2-Cre) exhibit increased susceptibility to Salmonella infection compared to control littermates. We demonstrate that Slc30a1-deficient macrophages are defective in intracellular killing, which correlated with reduced activation of nuclear factor kappa B and reduction in nitric oxide (NO) production. Notably, the model exhibits intracellular zinc accumulation, demonstrating that Slc30a1 is required for zinc export. We thus conclude that zinc export enables the efficient NO-mediated antibacterial activity of macrophages to control invading Salmonella.