MondoA coordinately regulates skeletal myocyte lipid homeostasis and insulin signaling

J Clin Invest. 2016 Sep 1;126(9):3567-79. doi: 10.1172/JCI87382. Epub 2016 Aug 8.

Abstract

Intramuscular lipid accumulation is a common manifestation of chronic caloric excess and obesity that is strongly associated with insulin resistance. The mechanistic links between lipid accumulation in myocytes and insulin resistance are not completely understood. In this work, we used a high-throughput chemical biology screen to identify a small-molecule probe, SBI-477, that coordinately inhibited triacylglyceride (TAG) synthesis and enhanced basal glucose uptake in human skeletal myocytes. We then determined that SBI-477 stimulated insulin signaling by deactivating the transcription factor MondoA, leading to reduced expression of the insulin pathway suppressors thioredoxin-interacting protein (TXNIP) and arrestin domain-containing 4 (ARRDC4). Depleting MondoA in myocytes reproduced the effects of SBI-477 on glucose uptake and myocyte lipid accumulation. Furthermore, an analog of SBI-477 suppressed TXNIP expression, reduced muscle and liver TAG levels, enhanced insulin signaling, and improved glucose tolerance in mice fed a high-fat diet. These results identify a key role for MondoA-directed programs in the coordinated control of myocyte lipid balance and insulin signaling and suggest that this pathway may have potential as a therapeutic target for insulin resistance and lipotoxicity.

MeSH terms

  • Animals
  • Arrestins / metabolism
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / physiology*
  • Biopsy
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins
  • Diet, High-Fat
  • Glucose / metabolism
  • Homeostasis
  • Insulin / metabolism*
  • Insulin Resistance / physiology
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lipid Metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscle Cells / metabolism*
  • Muscle Fibers, Skeletal / metabolism
  • Muscle, Skeletal / cytology*
  • Oligonucleotide Array Sequence Analysis
  • Rats
  • Signal Transduction
  • Thioredoxins / metabolism
  • Transfection
  • Triglycerides / metabolism

Substances

  • Arrdc4 protein, mouse
  • Arrestins
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Carrier Proteins
  • Cell Cycle Proteins
  • Insulin
  • Intracellular Signaling Peptides and Proteins
  • MONDOA protein, human
  • MondoA protein, mouse
  • MondoA protein, rat
  • TXNIP protein, human
  • TXNIP protein, rat
  • Triglycerides
  • Txnip protein, mouse
  • Thioredoxins
  • Glucose