Progesterone inhibits glucose uptake by affecting diverse steps of insulin signaling in 3T3-L1 adipocytes.
Maternal insulin resistance is essential for efficient provision of glucose to the fetus. Although elevation of placental hormones is known to relate to the development of insulin resistance, the precise underlying mechanism of maternal insulin resistance is unknown. Therefore, we examined the molecular mechanisms of progesterone causing insulin resistance in 3T3-L1 adipocytes. Progesterone at 10(-4) M, but not 10(-5) M, reduced the amount of IRS-1. As a result, insulin-induced phosphorylation of IRS-1, the association of IRS-1 with p85alpha, and subsequent phosphorylation of Akt1 and -2 was decreased moderately by 10(-4) M progesterone. Subsequently, insulin-induced translocation of GLUT4 to the plasma membrane evaluated by immunostaining on the plasma membrane sheet by confocal laser microscope was also decreased by 10(-4) M progesterone. In contrast, 2-[(3)H]deoxyglucose (2DG) uptake was markedly inhibited by both 10(-5) and 10(-4) M progesterone in a dose-dependent manner. Surprisingly, 2DG uptake elicited by adenovirus-mediated expression of constitutive-active mutant of PI 3-kinase (myr-p110) and Akt (myr-Akt) was suppressed by progesterone. Interestingly, insulin-induced tyrosine phosphorylation of Cbl and activation of TC10 were inhibited by progesterone at 10(-5) M. These results indicate that progesterone is implicated in insulin resistance during pregnancy by inhibiting the PI 3-kinase pathway at the step of 1) IRS-1 expression and 2) distal to Akt and 3) by suppressing the PI 3-kinase-independent pathway of TC10 activation by affecting Cbl phosphorylation.
Wada
Tsutomu
T
Dept. of Clinical Pharmacology, Univ. of Toyama, Japan.
Hori
Satoko
S
Sugiyama
Maine
M
Fujisawa
Eriko
E
Nakano
Tetsuro
T
Tsuneki
Hiroshi
H
Nagira
Kiyofumi
K
Saito
Shigeru
S
Sasaoka
Toshiyasu
T
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D000963:Antimetabolites; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D003847:Deoxyglucose; D005260:Female; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007328:Insulin / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D051379:Mice; D018613:Microscopy, Confocal; D051058:Oncogene Protein v-akt / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011247:Pregnancy; D011374:Progesterone / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D000963:Antimetabolites; D051275:Glucose Transporter Type 4; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; C495693:Slc2a4 protein, mouse; D011374:Progesterone; D003847:Deoxyglucose; D051058:Oncogene Protein v-akt; C503260:Rhoq protein, mouse; D020741:rho GTP-Binding Proteins; D005947:Glucose