Protein O-GlcNAcylation and the regulation of energy homeostasis: lessons from knock-out mouse models

Abstract

O-GlcNAcylation corresponds to the addition of N-Acetylglucosamine (GlcNAc) on serine or threonine residues of cytosolic, nuclear and mitochondrial proteins. This reversible modification is catalysed by a unique couple of enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). OGT uses UDP-GlcNAc produced in the hexosamine biosynthesis pathway, to modify proteins. UDP-GlcNAc is at the cross-roads of several cellular metabolisms, including glucose, amino acids and fatty acids. Therefore, OGT is considered as a metabolic sensor that post-translationally modifies proteins according to nutrient availability. O-GlcNAcylation can modulate protein–protein interactions and regulate protein enzymatic activities, stability or subcellular localization. In addition, it can compete with phosphorylation on the same serine or threonine residues, or regulate positively or negatively the phosphorylation of adjacent residues. As such, O-GlcNAcylation is a major actor in the regulation of cell signaling and has been implicated in numerous physiological and pathological processes. A large body of evidence have indicated that increased O-GlcNAcylation participates in the deleterious effects of glucose (glucotoxicity) in metabolic diseases. However, recent studies using mice models with OGT or OGA knock-out in different tissues have shown that O-GlcNAcylation protects against various cellular stresses, and indicate that both increase and decrease in O-GlcNAcylation have deleterious effects on the regulation of energy homeostasis.

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

“…Reciprocally, the use of adipocyte‐specific OGT knock‐out mice strengthened the marked interference of O ‐GlcNAcylation in adiposity and thus metabolic pathologies (for review, see [46]) (Figure 4). White adipose tissue (WAT) conditional OGT KO mice led to the conclusion that this glycosyltransferase enables a dialog between adipocytes and brain; 47 this axis drives hyperphagia and obesity when animals were placed on a high‐fat diet 47 .…”

“…Most of the current literature focuses on how OGT drives adipose tissue fat storage and mobilization, and biosynthesis of fatty acids. [46][47][48][49][50][51][52][53][54] Apart from that, almost everything remains to be done in the field. While few studies were dedicated to bile acids, 74,75 the other cholesterol derivatives among which vitamins of the group D, oxysterols, steroid and sex hormones (cortisol, aldosterone, testos-terone, progesterone, estriol, etc.)…”

“…14 Under its apparent simplicity, O-GlcNAcylation intervenes at many different levels in the regulation of cellular and tissue homeostasis, as well as at the level of a whole organism. 10,15 Unlike many glycosylations, O-GlcNAcylation is a highly dynamic modification (Figure 2).…”

“…Most of the current literature focuses on how OGT drives adipose tissue fat storage and mobilization, and biosynthesis of fatty acids 46–54 . Apart from that, almost everything remains to be done in the field.…”

Advanced polymer hydrogels that promote diabetic ulcer healing: mechanisms, classifications, and medical applications

“…In humans, this process is regulated by a pair of highly conserved enzymes: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). OGT catalyzes the reaction between UDP-GlcNAc and the hydroxyl groups of the above two amino acid residues to form amide bonds to participate in the modification process, while OGA is responsible for reversing this protein modification [ 51 ] (Fig. 3 ).…”