Loss of TSC complex enhances gluconeogenesis via upregulation of Dlk1-Dio3 locus miRNAs

Proc Natl Acad Sci U S A. 2020 Jan 21;117(3):1524-1532. doi: 10.1073/pnas.1918931117. Epub 2020 Jan 9.


Loss of the tumor suppressor tuberous sclerosis complex 1 (Tsc1) in the liver promotes gluconeogenesis and glucose intolerance. We asked whether this could be attributed to aberrant expression of small RNAs. We performed small-RNA sequencing on liver of Tsc1-knockout mice, and found that miRNAs of the delta-like homolog 1 (Dlk1)-deiodinase iodothyronine type III (Dio3) locus are up-regulated in an mTORC1-dependent manner. Sustained mTORC1 signaling during development prevented CpG methylation and silencing of the Dlk1-Dio3 locus, thereby increasing miRNA transcription. Deletion of miRNAs encoded by the Dlk1-Dio3 locus reduced gluconeogenesis, glucose intolerance, and fasting blood glucose levels. Thus, miRNAs contribute to the metabolic effects observed upon loss of TSC1 and hyperactivation of mTORC1 in the liver. Furthermore, we show that miRNA is a downstream effector of hyperactive mTORC1 signaling.

Keywords: CpG methylation; Dlk1-Dio3; glucose metabolism; mTOR; miRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism*
  • Genetic Loci
  • Genomic Imprinting
  • Gluconeogenesis / genetics
  • Gluconeogenesis / physiology*
  • Iodide Peroxidase / genetics
  • Iodide Peroxidase / metabolism*
  • Liver / metabolism
  • Male
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice
  • Mice, Knockout
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Sequence Analysis
  • Signal Transduction
  • Transcriptome
  • Tuberous Sclerosis Complex 1 Protein / genetics
  • Tuberous Sclerosis Complex 1 Protein / metabolism*
  • Up-Regulation*


  • Calcium-Binding Proteins
  • Dlk1 protein, mouse
  • MicroRNAs
  • Tsc1 protein, mouse
  • Tuberous Sclerosis Complex 1 Protein
  • iodothyronine deiodinase type III
  • Iodide Peroxidase
  • Mechanistic Target of Rapamycin Complex 1