Figure 8. MondoA directs myocyte fuel homeostatic checkpoint functions.

Proposed gene-regulatory (red arrows) and metabolic “checkpoint” responses (blue arrows) downstream of MondoA. MondoA is a glucose “sensor” that is directly activated by glycolytic metabolites that stimulate nuclear import of MondoA. Once activated, MondoA functions as a “brake” to limit carbon entry into the cell via increasing levels of TXNIP, an inhibitor of insulin signaling and glucose uptake. In addition, MondoA promotes energy storage through activation of enzymes involved in lipid and glycogen synthesis. Thus, MondoA may serve to limit carbon intake and fuel burning during conditions of “plenty.” However, in states of chronic nutrient excess, persistent activation of MondoA may become maladaptive, contributing to a vicious cycle of cellular lipid accumulation (TAG synthesis) and insulin resistance (TXNIP-mediated suppressive effects).