Protein O-GlcNAc Modification Links Dietary and Gut Microbial Cues to the Differentiation of Enteroendocrine L Cells

Ming Zhao; Kaiqun Ren; Xiwen Xiong; Meng Cheng; Zengdi Zhang; Zan Huang; Xiaonan Han; Xiaoyong Yang; Emilyn U. Alejandro; Hai-Bin Ruan

Cell Reports (Aug 2020)

Protein O-GlcNAc Modification Links Dietary and Gut Microbial Cues to the Differentiation of Enteroendocrine L Cells

Ming Zhao,
Kaiqun Ren,
Xiwen Xiong,
Meng Cheng,
Zengdi Zhang,
Zan Huang,
Xiaonan Han,
Xiaoyong Yang,
Emilyn U. Alejandro,
Hai-Bin Ruan

Affiliations

Ming Zhao: Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
Kaiqun Ren: Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA; College of Medicine, Hunan Normal University, Changsha, Hunan 410013, China
Xiwen Xiong: School of Forensic Medicine, Xinxiang Medical University, Xinxiang, Henan 453003, China
Meng Cheng: Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
Zengdi Zhang: Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
Zan Huang: Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
Xiaonan Han: Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
Xiaoyong Yang: Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06519, USA; Program in Integrative Cell Signaling and Neurobiology of Metabolism, Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06519, USA
Emilyn U. Alejandro: Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
Hai-Bin Ruan: Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA; Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455, USA; Corresponding author

Journal volume & issue: Vol. 32, no. 6
p. 108013

Abstract

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Summary: Intestinal L cells regulate a wide range of metabolic processes, and L-cell dysfunction has been implicated in the pathogenesis of obesity and diabetes. However, it is incompletely understood how luminal signals are integrated to control the development of L cells. Here we show that food availability and gut microbiota-produced short-chain fatty acids control the posttranslational modification on intracellular proteins by O-linked β-N-acetylglucosamine (O-GlcNAc) in intestinal epithelial cells. Via FOXO1 O-GlcNAcylation, O-GlcNAc transferase (OGT) suppresses expression of the lineage-specifying transcription factor Neurogenin 3 and, thus, L cell differentiation from enteroendocrine progenitors. Intestinal epithelial ablation of OGT in mice not only causes L cell hyperplasia and increased secretion of glucagon-like peptide 1 (GLP-1) but also disrupts gut microbial compositions, which notably contributes to decreased weight gain and improved glycemic control. Our results identify intestinal epithelial O-GlcNAc signaling as a brake on L cell development and function in response to nutritional and microbial cues.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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