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

Abstract

SUMMARY 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.

Glycaemia and body weight are regulated by sodium-glucose cotransporter 1 (SGLT1) expression via O-GlcNAcylation in the intestine

“…SGLT1 is involved in glucose absorption by the intestinal absorptive epithelial cells, and it regulates glucose-dependent incretin secretion from enteroendocrine cells such as GLP-1-secreting L cells and GIP-secreting K cells [ 10 ]. In the Ogt -VKO mice, incretin secretion was increased during fasting, as previously shown [ 31 ]. By contrast, glucose-dependent GLP-1 secretion was significantly suppressed in the Ogt -VKO mice, similarly to the Sglt1 -knockout mice.…”

Pancreatic β-Cell O-GlcNAc Transferase Overexpression Increases Susceptibility to Metabolic Stressors in Female Mice

“…The exogenous Ogt RNA level was also higher in females, potentially suggesting transcriptional or post-transcriptional regulatory differences between male and female transgenic animals. Overexpression of the same Ogt transgene in adipose or enteroendocrine L cells does not show sexual dimorphic expression [12,13]. Future studies are required to elucidate the sex-dependent mechanisms of Ogt transgene overexpression in islets and to explore possible mechanisms of post-transcriptional and stability regulation of Ogt.…”

“…Pancreatic β-cell Ogt overexpression (βOgtOE) is generated by crossing a mouse line expressing cre-recombinase under rat insulin promoter (rip-cre, from Dr. Pedro Herrera, University of Geneva) with a mouse line harboring a rat OGT transgene in the Rosa26 locus (Rosa26-STOPfloxed-Flag-HA-rOGT-IRES-eGFP from Xiaoyong Yang, Yale University). Ogt overexpression has been successfully induced in adipocytes or enteroendocrine L cells, using the Cre-lox system [12,13]. All mice were group housed on a 14:10 light-dark cycle.…”

Gut Microbiota: An Important Player in Type 2 Diabetes Mellitus

“…Previous studies found that SCFAs inhibited insulin signaling by activating G protein-coupled receptor 43 (GPR43) in adipocytes, thereby suppressing fat accumulation in adipose tissue and promoting energy metabolism in other tissues ( Kimura et al, 2013 ). In addition, SCFAs inhibited the expression of Neurogenin 3 through forkhead box O1 (FOXO1) O-GlcNAcylation and thus suppressed L cell development ( Zhao M. et al, 2020 ). The protein O-GlcNAcylation deficiency in intestinal epithelial cells promoted L cell hyperplasia and GLP-1 secretion in mice, thereby improving glucose metabolism.…”