Obesity-related insulin resistance is strongly associated with accumulation of neutral lipid in extra-adipose tissues. This phenomenon is particularly well-documented in skeletal muscle. The mechanistic underpinnings of this linkage are not fully understood. We hypothesized that fundamental homeostatic mechanisms exist to coordinately control cellular lipid stores and insulin-mediated glucose uptake. Previously, we found that the muscle-enriched transcription factor MondoA inhibits myocyte insulin signaling via induction of TXNIP and increases myocyte neutral lipid stores through an unknown mechanism. Current studies demonstrated that the activity of MondoA (a muscle-enriched relative of ChREBP) is regulated by nutrient (glucose and fructose) availability in human skeletal myocytes. Whole genome RNA-seq and ChIP-seq studies defined an array of MondoA target genes involved in insulin signaling, cellular nutrient storage pathways (triacylglyceride and glycogen synthesis), and hexosamine biosynthesis. In addition, MondoA regulates KLF10 and KLF11, known regulators of glucose homeostasis. Mice with muscle-specific genetic deletion of MondoA (msMondoA-/- mice) exhibited improved glucose tolerance and reduced muscle lipid accumulation in the context of diet-induced obesity (DIO). Insulin-stimulated glucose uptake was increased in muscles isolated from DIO msMondoA-/- mice vs. wild type controls. We conclude that MondoA serves to balance nutrient storage and catabolism by suppressing insulin signaling and shuttling fatty acids into triglyceride stores during conditions of “plenty.” However, with chronic nutrient excess, chronic activation of MondoA drives a vicious cycle of myocyte lipid accumulation and insulin resistance. Accordingly, MondoA signaling is a candidate target for new therapeutic strategies aimed at reducing insulin resistance and cellular lipotoxicity.
B. Ahn: None.
National Institute of Diabetes and Digestive and Kidney Diseases
