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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number108013
JournalCell reports
Volume32
Issue number6
DOIs
StatePublished - Aug 11 2020

Bibliographical note

Funding Information:
We thank Drs. Alessandro Bartolomucci, Maria Razzoli, and Pilar Ariza Guzman for help with the metabolic cages and EchoMRI analyses. This work was supported by the National Natural and Science Foundation of China , China ( 81770543 to H.-B.R. and U1904132 to X.X.), American Diabetes Association , United States ( 1-18-IBS-167 to H.-B.R.), and the NIH , United States ( R01 AI139420 and R21 AI140109 to H.-B.R., R21 DK112144 and R01 DK115720 to E.U.A., and R01 DK089098 and R01 DK102648 to X.Y.).

Publisher Copyright:
© 2020 The Author(s)

Keywords

  • GLP-1
  • L cells
  • O-GlcNAc
  • diabetes
  • obesity
  • short-chain fatty acids

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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