MondoA drives muscle lipid accumulation and insulin resistance

JCI Insight. 2019 Jul 9;5(15):e129119. doi: 10.1172/jci.insight.129119.

Abstract

Obesity-related insulin resistance is associated with intramyocellular lipid accumulation in skeletal muscle. We hypothesized that in contrast to current dogma, this linkage is related to an upstream mechanism that coordinately regulates both processes. We demonstrate that the muscle-enriched transcription factor MondoA is glucose/fructose responsive in human skeletal myotubes and directs the transcription of genes in cellular metabolic pathways involved in diversion of energy substrate from a catabolic fate into nutrient storage pathways including fatty acid desaturation and elongation, triacylglyeride (TAG) biosynthesis, glycogen storage, and hexosamine biosynthesis. MondoA also reduces myocyte glucose uptake by suppressing insulin signaling. Mice with muscle-specific MondoA deficiency were partially protected from insulin resistance and muscle TAG accumulation in the context of diet-induced obesity. These results identify MondoA as a nutrient-regulated transcription factor that under normal physiological conditions serves a dynamic checkpoint function to prevent excess energy substrate flux into muscle catabolic pathways when myocyte nutrient balance is positive. However, in conditions of chronic caloric excess, this mechanism becomes persistently activated leading to progressive myocyte lipid storage and insulin resistance.

Keywords: Glucose metabolism; Insulin signaling; Metabolism; Muscle Biology; Transcription.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
  • Cell Line
  • Disease Models, Animal
  • Female
  • Fructose / metabolism
  • Glucose / metabolism
  • Glycogen / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin Resistance / genetics
  • Insulin Resistance / physiology*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lipid Metabolism*
  • Lipids
  • Male
  • Metabolic Networks and Pathways / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle Fibers, Skeletal / metabolism
  • Muscle, Skeletal / metabolism*
  • Obesity / metabolism*
  • Signal Transduction
  • Transcription Factors / metabolism
  • Transcriptome
  • Triglycerides / biosynthesis

Substances

  • Arrdc4 protein, mouse
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Insulin
  • Intracellular Signaling Peptides and Proteins
  • Lipids
  • MLXIP protein, human
  • MondoA protein, mouse
  • Transcription Factors
  • Triglycerides
  • Fructose
  • Glycogen
  • Glucose