Estradiol-induced regulation of GLUT4 in 3T3-L1 cells: involvement of ESR1 and AKT activation

Autor(es)

Campello, Raquel S. ^[1] ; Fatima, Luciana A. ^[1] ; Barreto-Andrade, Joao Nilton ^[1] ; Lucas, Thais F. ^[2] ; Mori, Rosana C. ^[1] ; Porto, Catarina S. ^[2] ; Machado, Ubiratan F. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Biomed Sci, Dep Physiol & Biophys, Sao Paulo - Brazil

^[2] Univ Fed Sao Paulo, Escola Paulista Med, Dept Pharmacol, Sect Expt Endocrinol, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF MOLECULAR ENDOCRINOLOGY; v. 59, n. 3, p. 257-268, OCT 2017.
• Citações Web of Science: 4

Resumo

Impaired insulin-stimulated glucose uptake involves reduced expression of the GLUT4 (solute carrier family 2 facilitated glucose transporter member 4, SLC2A4 gene). 17 beta-estradiol (E-2) modulates SLC2A4/GLUT4 expression, but the involved mechanisms are unclear. Although E-2 exerts biological effects by binding to estrogen receptors 1/2 (ESR1/2), which are nuclear transcriptional factors; extranuclear effects have also been proposed. We hypothesize that E-2 regulates GLUT4 through an extranuclear ESR1 mechanism. Thus, we investigated the effects of E-2 upon (1) subcellular distribution of ESRs and the proto-oncogene tyrosine-protein kinases (SRC) involvement; (2) serine/ threonine-protein kinase (AKT) activation; (3) Slc2a4/GLUT4 expression and (4) GLUT4 subcellular distribution and glucose uptake in 3T3-L1 adipocytes. Differentiated 3T3-L1 adipocytes were cultivated or not with E-2 for 24 h, and additionally treated or not with ESR1-selective agonist (PPT), ESR1-selective antagonist (MPP) or selective SRC inhibitor (PP2). Subcellular distribution of ESR1, ESR2 and GLUT4 was analyzed by immunocytochemistry; Slc2a4 mRNA and GLUT4 were quantified by qPCR and Western blotting, respectively; plasma membrane GLUT4 translocation and glucose uptake were analyzed under insulin stimulus for 20 min or not. E-2 induced (1) translocation of ESR1, but not of ESR2, from nucleus to plasma membrane and AKT phosphorylation, effects mimicked by PPT and blocked by MPP and PP2; (2) increased Slc2a4/GLUT4 expression and (3) increased insulin-stimulated GLUT4 translocation and glucose uptake. In conclusion, E-2 treatment promoted a SRC-mediated nucleus-plasma membrane shuttle of ESR1, and increased AKT phosphorylation, Slc2a4/GLUT4 expression and plasma membrane GLUT4 translocation; consequently, improving insulin-stimulated glucose uptake. These results unravel mechanisms through which estrogen improves insulin sensitivity. (AU)

• Processo FAPESP: 12/04831-1 - Novos moduladores do controle glicêmico e do desenvolvimento de complicações crônicas no Diabetes mellitus: perspectivas preventivas e terapêuticas
• Beneficiário: Ubiratan Fabres Machado
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 12/24210-1 - REGULAÇÃO DA EXPRESSÃO DE Slc2a4/GLUT4 PELO 17²-ESTRADIOL
• Beneficiário: Raquel Saldanha Campello
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado