title: Altered subcellular distribution of estrogen receptor alpha is implicated in estradiol-induced dual regulation of insulin signaling in 3T3-L1 adipocytes.
abstract: We investigated the mechanisms by which estrogen alters insulin signaling in 3T3-L1 adipocytes. Treatment with 17beta-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 Ser(307), which was abolished by treatment with a c-Jun NH(2)-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 alpha at the plasma membrane at 10(-8) m, but increased it at 10(-5) m. In contrast, the subcellular distribution of estrogen receptor beta 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 Ser(307) via a c-Jun NH(2)-terminal kinase-dependent pathway, and that the subcellular redistribution of estrogen receptor alpha in response to E2 may explain the dual effect of E2.
authors.affiliation: Department of Clinical Pharmacology, University of Toyama, Japan.
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Nagira
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Sasaoka
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Wada
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Fukui
authors.forename: Mariko
authors.initials: M
authors.lastname: Ikubo
authors.forename: Satoko
authors.initials: S
authors.lastname: Hori
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsuneki
authors.forename: Shigeru
authors.initials: S
authors.lastname: Saito
authors.forename: Masashi
authors.initials: M
authors.lastname: Kobayashi
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000008:administration & dosage / Q000502:physiology*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D020033:Protein Isoforms; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015290:Second Messenger Systems / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013347:Subcellular Fractions
chemical_list: D047628:Estrogen Receptor alpha; D007328:Insulin; D020033:Protein Isoforms; D004958:Estradiol; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose