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

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 ?-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.

SUBMITTER: Zhao M 

PROVIDER: S-EPMC7457433 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature