Intestinal Metrnl released into the gut lumen acts as a local regulator for gut antimicrobial peptides

Abstract

Aim: Metrnl is a novel secreted protein, but its physiological roles remain elusive. In this study, we investigated the tissue expression pattern of Metrnl in humans and explored its possible physiological role in the tissues with most highly expressed levels. Methods: A human tissue microarray containing 19 types of tissues from 69 donors was used to examine the tissue expression pattern of Metrnl, and the expression pattern was further verified in fresh human and mouse tissues. Intestinal epithelial cell-specific Metrnl knockout mice were generated, which were used to analyze the physiological roles of Metrnl. Results: Metrnl was the most highly expressed in the human gastrointestinal tract, and was specifically expressed in the intestinal epithelium. Consistent with this, Metrnl mRNA was also most highly expressed in the mouse gastrointestinal tract among the 14 types of tissues tested. In the intestinal epithelial cell-specific Metrnl knockout mice, the Metrnl levels in the gut fluid were significantly reduced, whereas the Metrnl serum levels showed a trend towards a reduction, but this change was not statistically significant. This cell-specific deletion of Metrnl did not affect body weight, food intake, blood glucose, colon length and histology, intestinal permeability, mucus content or mucin 2 expression under physiological conditions, but statistically decreased the expression of antimicrobial peptides, such as regenerating islet-derived 3 gamma (Reg3g) and lactotransferrin. Conclusion: Metrnl is highly expressed in the intestinal epithelial cells of humans and mice, which mainly contributes to the local gut Metrnl levels and affects the serum Metrnl level to a lesser extent. Metrnl plays a role in maintaining gut antimicrobial peptides.

Evaluation of Two Commercial Enzyme-Linked Immunosorbent Assay Kits for the Detection of Human Circulating Metrnl

“…[1][2][3][4] Metrnl gene is located on human chromosome 17q25.3 and the protein is predicted to contain 311 amino acids, with a signal peptide of 45 amino acids and without any transmembrane region, suggesting a mature protein of 266 amino acids (～30 kDa) when secreted. 1) First described in 2012, 2) Metrnl is soon being recognized as serving important roles in neural development, 2,5) white adipose browning 6) and insulin sensitization.…”

“…1) First described in 2012, 2) Metrnl is soon being recognized as serving important roles in neural development, 2,5) white adipose browning 6) and insulin sensitization. 7) Besides, it might be involved in both innate and acquired immune response, 8) in maintaining gut antimicrobial peptides 4) as well as in osteoblast function. 9) Our previous studies showed that Metrnl is highly expressed in white adipose tissue in both rodents and humans and plays important roles in adipose biology.…”

Characterization of the Serum Levels of Meteorin-like in Patients with Inflammatory Bowel Disease and its Association with Inflammatory Cytokines

“…Li et al demonstrated that, Metrnl is highly expressed in the gastrointestinal tract of normal donors as well as mice. On the other hand, they produced intestinal epithelial cell-speci c knockout mice, which showed no signi cant serum reduction, despite the reduction of Metrnl expression in the gastrointestinal tract [16]. A recent study performed by Zuo et al reported that Metrnl expression is higher in mesenteric adipose tissue (MAT) of the CD patients compared to the controls.…”

“…In addition, Metrnl is expressed in other tissues including muscle, liver, heart, spleen, and central nervous system (CNS). Moreover, the activated macrophages produced Metrnl, which by this fact, Metrnl may connected to the in ammatory disorders such as IBD [16]. A few studies have been done on tissue Metrnl levels in IBD disease.…”

Characterization of the Serum Levels of Meteorin-like in Patients with Inflammatory Bowel Disease and its Association with Inflammatory Cytokines

“…Moreover, the activated macrophages produced Metrnl, which by this fact, it may be connected to the in ammatory disorders such as IBD [16]. A few studies have been conducted on tissue Metrnl levels in IBD disease.…”