TAZ couples Hippo/Wnt signalling and insulin sensitivity through Irs1 expression

Nat Commun. 2019 Jan 24;10(1):421. doi: 10.1038/s41467-019-08287-x.

Abstract

Insulin regulates blood glucose levels by binding its receptor and stimulating downstream proteins through the insulin receptor substrate (IRS). Impaired insulin signalling leads to metabolic syndrome, but the regulation of this process is not well understood. Here, we describe a novel insulin signalling regulatory pathway involving TAZ. TAZ upregulates IRS1 and stimulates Akt- and Glut4-mediated glucose uptake in muscle cells. Muscle-specific TAZ-knockout mice shows significantly decreased Irs1 expression and insulin sensitivity. Furthermore, TAZ is required for Wnt signalling-induced Irs1 expression, as observed by decreased Irs1 expression and insulin sensitivity in muscle-specific APC- and TAZ-double-knockout mice. TAZ physically interacts with c-Jun and Tead4 to induce Irs1 transcription. Finally, statin administration decreases TAZ, IRS1 level and insulin sensitivity. However, in myoblasts, the statin-mediated decrease in insulin sensitivity is counteracted by the expression of a constitutively active TAZ mutant. These results suggest that TAZ is a novel insulin signalling activator that increases insulin sensitivity and couples Hippo/Wnt signalling and insulin sensitivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose
  • Cell Line
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Glucose / metabolism
  • Glucose Transporter Type 4 / metabolism
  • HEK293 Cells
  • Humans
  • Insulin / metabolism
  • Insulin Receptor Substrate Proteins / metabolism*
  • Insulin Resistance / physiology*
  • Mice
  • Mice, Knockout
  • Muscle Cells / metabolism
  • Muscle, Skeletal / metabolism
  • Mutagenesis, Site-Directed
  • Myoblasts / metabolism
  • Pharmaceutical Vehicles / administration & dosage
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction*
  • Simvastatin / administration & dosage
  • Simvastatin / pharmacology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Up-Regulation
  • Wnt Signaling Pathway

Substances

  • Blood Glucose
  • Glucose Transporter Type 4
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • Pharmaceutical Vehicles
  • Taz protein, mouse
  • Transcription Factors
  • Simvastatin
  • Hippo protein, mouse
  • Protein-Serine-Threonine Kinases
  • Glucose