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Altered Subcellular Distribution of Estrogen Receptor Is Implicated in Estradiol-Induced Dual Regulation of Insulin Signaling in 3T3-L1 Adipocytes

Departments of Obstetrics and Gynecology (K.N., S.S.) and Clinical Pharmacology (T.W., S.H., H.T., T.S.) and First Department of Medicine (K.F., M.I., M.K.), University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan

Address all correspondence and requests for reprints to: Dr. Toshiyasu Sasaoka, Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan. E-mail: tsasaoka-tym{at}umin.ac.jp.

We investigated the mechanisms by which estrogen alters insulin signaling in 3T3-L1 adipocytes. Treatment with 17ß-estradiol (E2) did not affect insulin-induced tyrosine phosphorylation of insulin receptor. E2 enhanced insulin-induced tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1), IRS-1/p85 association, phosphorylation of Akt, and 2-deoxyglucose uptake at 10^–8 M, but inhibited these effects at 10^–5 M. A concentration of 10^–5 M E2 enhanced insulin-induced phosphorylation of IRS-1 at Ser³⁰⁷, which was abolished by treatment with a c-Jun NH₂-terminal kinase inhibitor. In addition, the effect of E2 was abrogated by pretreatment with a specific estrogen receptor antagonist, ICI182,780. Membrane-impermeable E2, E2-BSA, did not affect the insulin-induced phosphorylation of Akt at 10^–8 M, but inhibited it at 10^–5 M. Furthermore, E2 decreased the amount of estrogen receptor at the plasma membrane at 10^–8 M, but increased it at 10^–5 M. In contrast, the subcellular distribution of estrogen receptor ß was not altered by the treatment. These results indicate that E2 affects the metabolic action of insulin in a concentration-specific manner, that high concentrations of E2 inhibit insulin signaling by modulating phosphorylation of IRS-1 at Ser³⁰⁷ via a c-Jun NH₂-terminal kinase-dependent pathway, and that the subcellular redistribution of estrogen receptor in response to E2 may explain the dual effect of E2.

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