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

Cell Rep. 2020 Aug 11;32(6):108013. doi: 10.1016/j.celrep.2020.108013.

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.

Keywords: GLP-1; L cells; O-GlcNAc; diabetes; obesity; short-chain fatty acids.

Publication types

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

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Caco-2 Cells
  • Cell Differentiation*
  • Cues
  • Diet*
  • Enteroendocrine Cells / cytology
  • Enteroendocrine Cells / metabolism*
  • Fatty Acids, Volatile / metabolism
  • Forkhead Box Protein O1 / metabolism
  • Gastrointestinal Microbiome*
  • Glucagon-Like Peptide 1 / metabolism
  • Humans
  • Intestinal Mucosa / metabolism
  • Mice
  • N-Acetylglucosaminyltransferases / metabolism*
  • Nerve Tissue Proteins / metabolism
  • Protein Processing, Post-Translational
  • Signal Transduction

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Fatty Acids, Volatile
  • Forkhead Box Protein O1
  • Nerve Tissue Proteins
  • Neurog3 protein, mouse
  • Glucagon-Like Peptide 1
  • N-Acetylglucosaminyltransferases
  • O-GlcNAc transferase