Growth Hormone Inhibition of Glucose Uptake in Adipocytes Occurs without Affecting GLUT4 Translocation through an Insulin Receptor Substrate-2-Phosphatidylinositol 3-Kinase-dependent Pathway

Jeffrey E. Pessin,Hideyuki Sakoda,Kazuhiro Chida,Tomomi Ogata,Kouhei Kasahara,Naoko Sasaki-Suzuki,Shin-Ichiro Takahashi,Kiyoshi Arai,Tomoichiro Asano,Fumihiko Hakuno

doi:10.1074/jbc.m808282200

Abstract

Growth hormone (GH) pretreatment of 3T3-L1 adipocytes resulted in a concentration- and time-dependent inhibition of insulin-stimulated glucose uptake. Surprisingly, this occurred without significant effect on insulin-stimulated glucose transporter (GLUT) 4 translocation or fusion with the plasma membrane. In parallel, the inhibitory actions of chronic GH pretreatment also impaired insulin-dependent activation of phosphatidylinositol (PI) 3-kinase bound to insulin receptor substrate (IRS)-2 but not to IRS-1. In addition, insulin-stimulated Akt phosphorylation was inhibited by GH pretreatment. In contrast, overexpression of IRS-2 or expression of a constitutively active Akt mutant prevented the GH-induced insulin resistance of glucose uptake. Moreover, small interfering RNA-mediated IRS-2 knockdown also inhibited insulin-stimulated Akt activation and glucose uptake without affecting GLUT4 translocation and plasma membrane fusion. Together, these data support a model in which chronic GH stimulation inhibits insulin-dependent activation of phosphatidylinositol 3-kinase through a specific interaction of phosphatidylinositol 3-kinase bound to IRS-2. This inhibition leads to suppression of Akt activation coupled to glucose transport activity but not translocation or plasma membrane fusion of GLUT4.

Highlights

Insulin is the major anabolic hormone whose action plays pivotal roles in tissue development, growth, and the maintenance of glucose homeostasis
Chronic Growth hormone (GH) Pretreatment Inhibits Insulin-stimulated Glucose Uptake in 3T3-L1 Adipocytes—It has been reported that chronic GH pretreatment inhibits insulin-dependent glucose uptake in cultured adipocytes (24)
Fully differentiated 3T3-L1 adipocytes were pretreated with various concentrations of GH for 24 h and subsequently subjected to an acute (15 min) stimulation with 0.1 nM insulin

Summary

Introduction

Insulin is the major anabolic hormone whose action plays pivotal roles in tissue development, growth, and the maintenance of glucose homeostasis. We showed that chronic GH pretreatment inhibits insulin-induced glucose uptake without affecting GLUT4 translocation, through the reduction of IRS-2-associated PI 3-kinase activity. 3T3-L1 adipocytes were electropotime-, and concentration-dependent inhibition of insulin-stim- rated with myc-GLUT4-GFP-expressing plasmids, and the cell ulated glucose uptake.

Results

Conclusion