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

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

Author Campello, Raquel S. Google Scholar
Fatima, Luciana A. Google Scholar
Barreto-Andrade, Joao Nilton Google Scholar
Lucas, Thais F. Autor UNIFESP Google Scholar
Mori, Rosana C. Google Scholar
Porto, Catarina S. Autor UNIFESP Google Scholar
Machado, Ubiratan F. Google Scholar
Abstract 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.
Keywords extranuclear ESR1
xmlui.dri2xhtml.METS-1.0.item-coverage Bristol
Language English
Sponsor FAPESP (Sao Paulo State Foundation for Research)
Grant number FAPESP: 2012/24210-1
FAPESP: 2012/04831-1
FAPESP: 2016/15603-1
Date 2017
Published in Journal Of Molecular Endocrinology. Bristol, v. 59, n. 3, p. 257-268, 2017.
ISSN 0952-5041 (Sherpa/Romeo, impact factor)
Publisher Bioscientifica Ltd
Extent 257-268
Access rights Closed access
Type Article
Web of Science ID WOS:000417615000008

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