O‐GlcNAcylation: a bridge between glucose and cell differentiation

Glucose is the major energy supply and a critical metabolite for most cells and is especially important when cell is differentiating. High or low concentrations of glucose enhances or inhibits the osteogenic, chondrogenic and adipogenic differentiation of cell via the insulin, transforming growth factor-β and peroxisome proliferator-activated receptor γ pathways, among others. New evidence implicates the hexosamine biosynthetic pathway as a mediator of crosstalk between glucose flux, cellular signalling and epigenetic regulation of cell differentiation. Extracellular glucose flux alters intracellular O-GlcNAcylation levels through the hexosamine biosynthetic pathway. Signalling molecules that are important for cell differentiation, including protein kinase C, extracellular signal-regulated kinase, Runx2, CCAAT/enhancer-binding proteins, are modified by O-GlcNAcylation. Thus, O-GlcNAcylation markedly alters cell fate during differentiation via the post-transcriptional modification of proteins. Furthermore, O-GlcNAcylation and phosphorylation show complex interactions during cell differentiation: they can either non-competitively occupy different sites on a substrate or competitively occupy a single site or proximal sites. Therefore, the influence of glucose on cell differentiation via O-GlcNAcylation offers a potential target for controlling tissue homoeostasis and regeneration in ageing and disease. Here, we review recent progress establishing an emerging relationship among glucose concentration, O-GlcNAcylation levels and cell differentiation.