Insulin Induces REDD1 Expression through Hypoxia-inducible Factor 1 Activation in Adipocytes

Claire Regazzetti,Frédéric Bost,Yannick Le Marchand-Brustel,Jean-François Tanti,Sophie Giorgetti-Peraldi

doi:10.1074/jbc.m109.047688

Abstract

REDD1 (regulated in development and DNA damage responses) is essential for the inhibition of mTORC1 (mammalian target of rapamycin complex) signaling pathway in response to hypoxia. REDD1 expression is regulated by many stresses such as hypoxia, oxidative stress, and energy depletion. However, the regulation of REDD1 expression in response to insulin remains unknown. In the present study, we demonstrate that in murine and in human adipocytes, insulin stimulates REDD1 expression. Insulin-induced REDD1 expression occurs through phosphoinositide 3-kinase/mTOR-dependent pathways. Moreover, using echinomycin, a hypoxia-inducible factor 1 (HIF-1) inhibitor, and HIF-1alpha small interfering RNA, we demonstrate that insulin stimulates REDD1 expression only through the transcription factor HIF-1. In conclusion, our study shows that insulin stimulates REDD1 expression in adipocytes.

Highlights

Mammalian target of rapamycin2 integrates several extrinsic signals that regulate cell growth and metabolism. mTOR is present in two multiprotein complexes: mTORC1, consisting of mTOR, Raptor, PRAS40, and mLST8/G␤L; and mTORC2, composed of mTOR, LST8/ G␤L, Rictor, mSin1, and Protor. mTORC1 regulates cell growth through S6 kinase 1 and eIF-4E-binding protein 1, whereas mTORC2 modulates cell survival by phosphorylating Akt/protein kinase B. mTOR complexes are regulated by TSC1/TCS2, a GTPase-activating protein for the Rasrelated small G protein Rheb, which regulates mTOR activation [1]
Insulin Induces REDD1 Expression in Adipocytes—We have investigated the effect of prolonged insulin stimulation on REDD1 expression in adipocytes
We show that the expression of a mTOR inhibitor, REDD1, is induced by insulin in murine and human adipocytes

Summary

Introduction

Mammalian target of rapamycin (mTOR)2 integrates several extrinsic signals that regulate cell growth and metabolism. mTOR is present in two multiprotein complexes: mTORC1, consisting of mTOR, Raptor, PRAS40, and mLST8/G␤L; and mTORC2, composed of mTOR, LST8/ G␤L, Rictor, mSin1, and Protor. mTORC1 regulates cell growth through S6 kinase 1 and eIF-4E-binding protein 1, whereas mTORC2 modulates cell survival by phosphorylating Akt/protein kinase B. mTOR complexes are regulated by TSC1/TCS2, a GTPase-activating protein for the Rasrelated small G protein Rheb, which regulates mTOR activation [1]. Human adipocytes were stimulated with insulin for 16 h in normoxia or in hypoxia in the absence or presence of inhibitors, and REDD1 expression was detected by immunoblotting. In contrast to human adipocytes, in 3T3-L1 adipocytes, inhibition of ERK by U0126 partially inhibited the expression of REDD1 in response to insulin in normoxia, without any significant effect in hypoxia (Fig. 4C).

Results

Conclusion