Journal
CELL REPORTS
Volume 32, Issue 6, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2020.108013
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Funding
- National Natural and Science Foundation of China, China [81770543, U1904132]
- American Diabetes Association, United States [1-18-IBS-167]
- NIH, United States [R01 AI139420, R21 AI140109, R21 DK112144, R01 DK115720, R01 DK089098, R01 DK102648]
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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 beta-N-acetylglucosamine (O-GIcNAc) 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.
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