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 journalArticle

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

Keywords

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

PubMed: MeSH publication types

  • Journal Article

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