4.7 Article

L-cell Arntl is required for rhythmic glucagon-like peptide-1 secretion and maintenance of intestinal homeostasis

期刊

MOLECULAR METABOLISM
卷 54, 期 -, 页码 -

出版社

ELSEVIER
DOI: 10.1016/j.molmet.2021.101340

关键词

Circadian; Colon; GLP-1; GLP-2; Immunity; Inflammation; Microbiome

资金

  1. University of Toronto, for the ARNTL [Gcg-CreERT2/thorn]
  2. Ontario Graduate Scholarship program
  3. Banting and Best Diabetes Centre (University of Toronto)
  4. Canadian Institutes of Health Research [PJT-14853]
  5. Ontario Graduate Scholarship
  6. Banting and Best Diabetes Centre
  7. Biological Rhythms Training Program (University of Toronto)
  8. Tier I Canada Research Chair
  9. (Digestive Tract and Disease) Centre - Canadian Foundation for Innovation and Ontario Research Fund [19442, 30961]

向作者/读者索取更多资源

The study highlights the crucial role of Arntl in regulating time-dependent GLP-1 secretion in intestinal L-cells, as well as its significant impact on the intestinal environment.
Objective: Recent studies using whole-body clock-disrupted animals identified a disruption in the circadian rhythm of the intestinal L-cell incretin hormone, glucagon-like peptide-1 (GLP-1). Although GLP-1 plays an essential role in metabolism through enhancement of both glucosestimulated insulin secretion and satiety, recent evidence has also demonstrated its importance in regulating intestinal and microbial homeostasis. Therefore, using in vivo and in vitro models, this study assessed the role of the core circadian clock gene Arntl in the regulation of time-dependent GLP-1 secretion and its impact on the intestinal environment. Methods: Oral glucose tolerance tests were conducted at zeitgeber time 2 and 14 in control and inducible Gcg-Arntl knockout (KO) mice. Colonic intraepithelial lymphocytes were isolated, mucosal gene expression analysis was conducted, and 16S rRNA gene sequencing of colonic feces as well as analysis of microbial metabolites were performed. Time-dependent GLP-1 secretion and transcriptomic analysis were conducted in murine (m) GLUTag L-cells following siRNA-mediated knockdown of Arntl. Results: Gcg-Arntl KO mice displayed disrupted rhythmic release of GLP-1 associated with reduced secretion at the established peak time point. Analysis of the intestinal environment in KO mice revealed a decreased proportion of CD4+ intraepithelial lymphocytes in association with increased proinflammatory cytokine gene expression and increased colonic weight. Moreover, increased Actinobacteria within the colonic microbiome was found following L-cell Arntl disruption, as well as reductions in the microbial products, short chain fatty acids, and bile acids. Finally, siRNA-mediated knockdown of Arntl in mGLUTag L-cells resulted in both impaired time-dependent GLP-1 secretion and the disruption of pathways related to key cellular processes. Conclusions: These data establish, for the first time, the essential role of Arntl in the intestinal L-cell in regulating time-dependent GLP-1 secretion. Furthermore, this study revealed the integral role of L-cell Arntl in mediating the intestinal environment, which ultimately may provide novel insight into the development of therapeutics for the treatment of intestinal and metabolic disorders. (c) 2021 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.7
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据