Control of lipid metabolism by the dynamic and nutrient-dependent post-translational modification O-GlcNAcylation

O-GlcNAcylation is a post-translational modification belonging to the large group of glycosylations. It consists of the modification of cytoplasmic, nuclear, and mitochondrial proteins with a single N-acetylglucosamine residue by O-GlcNAc transferase (OGT). Despite its structural simplicity, O-GlcNAcylation orchestrates many functions inside the cell. This modification regulates fatty acids synthesis, fat storage, and utilization. The generation of white and brown adipocyte-OGT knock-out mice has highlighted the marked interference of O-GlcNAcylation in adiposity and, as a consequence, in metabolic pathologies. OGT is more especially involved in the regulation of lipolysis, and thermogenesis in brown adipose tissue. In addition, O-GlcNAcylation directly regulates fatty acid synthase, the main enzyme responsible for fatty acids synthesis, and other lipogenic enzymes and transcription factors. Nevertheless, only a few studies reported connections between O-GlcNAcylation and homeostasis of cholesterol or its derivatives. This knowledge gap is surprising due to the crucial importance of cholesterol in structuring animal biological membranes and as a precursor of a wide variety of biological compounds. Here, we review the current literature about this topic and discuss future prospects in the field.Key points As a PTM, O-GlcNAcylation exponentially expands protein functions. O-GlcNAcylation orchestrates many biological functions in living beings including metabolic fluxes. O-GlcNAcylation is crucial for fat storage and mobilization, and for fatty acid synthesis but its function in the metabolism of other lipid compounds is less documented.