TY - JOUR
T1 - Growth hormone inhibition of glucose uptake in adipocytes occurs without affecting GLUT4 translocation through an insulin receptor substrate-2-phosphatidylinositol 3-kinase-dependent pathway
AU - Sasaki-Suzuki, Naoko
AU - Arai, Kiyoshi
AU - Ogata, Tomomi
AU - Kasahara, Kouhei
AU - Sakoda, Hideyuki
AU - Chida, Kazuhiro
AU - Asano, Tomoichiro
AU - Pessin, Jeffrey E.
AU - Hakuno, Fumihiko
AU - Takahashi, Shin Ichiro
PY - 2009/3/6
Y1 - 2009/3/6
N2 - 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 bur not translocation or plasma membrane fusion of GLUT4.
AB - 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 bur not translocation or plasma membrane fusion of GLUT4.
UR - http://www.scopus.com/inward/record.url?scp=65249086321&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=65249086321&partnerID=8YFLogxK
U2 - 10.1074/jbc.M808282200
DO - 10.1074/jbc.M808282200
M3 - Article
C2 - 19122000
AN - SCOPUS:65249086321
SN - 0021-9258
VL - 284
SP - 6061
EP - 6070
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 10
ER -