In the stressed heart, metabolic remodeling precedes most, if not all, other pathophysiological changes [1]. When the heart is not stressed, it relies on fat for energy provision, with glucose being an additional energy source, while lactate, ketone bodies, and amino acids contribute as well, but do so only to a small extent. As a metabolic omnivore, the heart switches its nutrient preference towards more glucose under stress. After uptake, glucose is converted to pyruvate in the glycolytic pathway (Fig. 1). Pyruvate either enters the mitochondria for oxidation, or it is reduced to lactate. In addition to glycolysis, the carbons of glucose may be shunted into ancillary metabolic pathways, including hexosamine biosynthetic pathway (HBP), pentose phosphate pathway, glycogen synthetic pathway, and serine biosynthetic pathway.

Since its first discovery in 1984, HBP has been shown to play critical roles in various diseases, including cardiovascular disease, diabetes, and cancer. HBP flux is governed by its rate-limiting enzyme GFAT (Glutamine: fructose-6-phosphate aminotransferase)(Fig. 1). As the end product of HBP, UDP-GlcNAc serves as substrate for both O-GlcNAcylation and N-glycosylation, two common posttranslational modifications. O-GlcNAcylation is regulated by two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which conjugate the GlcNAc moiety to and remove it from serine and threonine residues of target proteins, respectively. In addition to targets like NFAT, CAMKII, HDAC4, and FoxO1, the above three key O-GlcNAcylation enzymes themselves can be modified by O-GlcNAcylation, yielding a tight and precise control of this posttranslational modification.