A recent publication in Cell Reports by Drs. Ming Zhao and Hai-Bin Ruan at the University of Minnesota, twin cities employed cutting-edge molecular biology approach to determine whether O-linked-N-acetylglucosaminylation (O-GlcNAcylation) in intestinal epithelium controls enteroendocrine L cell differentiation and systemic glucose metabolism. L cells regulate a wide range of metabolic processes by secreting hormone glucagon-like peptide 1 (GLP-1), and L-cell dysfunction has been implicated in the pathogenesis of obesity and diabetes. Therefore, GLP-1 and GLP-1R have been recognized as important therapeutic targets for obesity and diabetes. However, it is incompletely understood how L cells development is regulated and disrupted by luminal signals. Here this current research shows that high-fat diet 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. Genetically depletion of O-GlcNAcylation in intestinal epithelial cells in mice causes L cell hyperplasia and increased secretion of GLP-1. Mechanistically, O-GlcNAcylation on FOXO1 suppresses expression of the lineage-specifying transcription factor Neurogenin 3 and, in turn, L cell differentiation from enteroendocrine progenitors. In addition, O-GlcNAc deficiency disrupts gut microbial compositions, which notably contributes to decreased weight gain and improved glycemic control. These results identify intestinal epithelial O-GlcNAc signaling as a brake on L cell development and function in response to nutritional and microbial cues. Dr. Xiaoyong Yang at Yale University also provided supports on this work. (Written by Dr. Ming Zhao)
