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

Jun-Ha Hwang,Mi Ran Byun,Eun Sook Hwang,Sung A Moon,Hyo Kyung Kim,Jung Il Park,Michael B Yaffe,Ho Taek Oh,A Rum Kim,Kyung Min Kim,Jeong-Ho Hong,Hana Jeong

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.

Highlights

Insulin regulates blood glucose levels by binding its receptor and stimulating downstream proteins through the insulin receptor substrate (IRS)
Insulindependent glucose utilization, which primarily occurs in tissues such as muscle, is a process that requires activation of the insulin receptor (IR) and the sequential stimulation of IRS1/2, Akt kinase, and substrates such as ribosomal S6 kinase (S6K) and Akt substrate of 160 kDa (AS160)[23]
The results reveal that Transcriptional coactivator with PDZ-binding motif (TAZ) stimulates insulin signalling through IRS1

Summary

Introduction

Insulin regulates blood glucose levels by binding its receptor and stimulating downstream proteins through the insulin receptor substrate (IRS). TAZ upregulates IRS1 and stimulates Akt- and Glut4-mediated glucose uptake in muscle cells. 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. It has been reported that AMPK phosphorylates and stabilises AMOTL1, which contributes to YAP inhibition[22] These reports suggest that TAZ/ YAP function as mediators of metabolic signalling. We report that TAZ facilitated glucose uptake and increased insulin sensitivity in response to Hippo/Wnt signalling, suggesting that TAZ is a novel regulator of the insulin signalling pathway. The insulin sensitivity-lowering effect of statins, a class of lipid-lowering medications, is regulated via TAZ

Methods

Results

Conclusion