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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Estrogen Receptor 1 Agonist PPT Stimulates Slc2a4 Gene Expression and Improves Insulin-Induced Glucose Uptake in Adipocytes

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Campello, R. S. [1] ; Alves-Wagner, A. B. [1] ; Lucas, T. F. [2] ; Mori, R. C. [1] ; Furuya, D. T. [1] ; Porto, C. S. [2] ; Machado, U. F. [1]
Total Authors: 7
[1] Univ Sao Paulo, Inst Biomed Sci, Dept Physiol & Biophys, BR-05508900 Sao Paulo - Brazil
[2] Univ Fed Sao Paulo, Dept Pharmacol, Escola Paulista Med, Sect Expt Endocrinol, Sao Paulo - Brazil
Total Affiliations: 2
Document type: Review article
Source: CURRENT TOPICS IN MEDICINAL CHEMISTRY; v. 12, n. 19, p. 2059-2069, OCT 2012.
Web of Science Citations: 12

Type 2 diabetes mellitus is characterized by disruption in glycemic homeostasis, involving impaired insulin-induced glucose disposal. For that, reduced glucose transporter GLUT4, encoded by Slc2a4 gene, plays a fundamental role. Conversely, increase in Slc2a4/GLUT4 expression improves glycemic homeostasis. Recent studies have proposed that estradiol is able to modulate Slc2a4 expression, according to distinct effects upon estrogen receptors ESR1/ESR2. We hypothesize that ESR1-agonist effect could stimulate Slc2a4 expression; thus, increasing cellular glucose disposal, which could be beneficial to glycemic control. Differentiated 3T3-L1 adipocytes were treated (24 hours) with selective ESR1-agonist PPT 1,3,5-tris(4-hydroxyphenyl)-4- propyl-1H-pyrazole, selective ESR1-antagonist MPP 1,3-Bis(4-hydroxyphenyl)-4- methyl-5-{[}4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride, and selective ESR2 agonist DPN 2,3-bis(4-Hydroxyphenyl)-propionitrile, with/without 17 beta-estradiol (E2). We analyzed Slc2a4 mRNA (real time PCR) and GLUT4 protein (Western blotting) expression, transcriptional activity of the Slc2a4 repressor Nuclear Factor-kappa B (NF-kappa B) (electrophoretic mobility shift assay), and cellular glucose disposal (2-deoxi-D-{[}H-3]glucose uptake, 2-DG). ESR1-agonist PPT enhanced Slc2a4/GLUT4 expression (similar to 30%) in the absence or presence of 0.1 and 10 nmol/L E2, and decreased the NF-kappa B binding activity (similar to 50%). Conversely, ESR1-antagonist MPP, together with E2, decreased Slc2a4/GLUT4 expression (20-40%) and increased NF-kappa B binding activity (similar to 30%). Furthermore, treatment with ESR2-agonist DPN decreased Slc2a4/GLUT4 expression (20-50%). 2-DG uptake was modulated in parallel to that observed in GLUT4 protein. The present results reveal that ESR1 activity enhances, whereas ESR2 activity represses, Slc2a4/GLUT4 expression. These effects are partially mediated by NF-kappa B, and allow parallel changes in adipocyte glucose disposal. Furthermore, the data provide evidences that ESR1-agonist PPT, as a Slc2a4/GLUT4 enhancer, can be a promising coadjuvant d(r)ug for diabetes mellitus therapy. (AU)

FAPESP's process: 07/50554-1 - Glucose transporters and diabetes mellitus: contribution to the knowledge of glycemic control and chronic diseases development
Grantee:Ubiratan Fabres Machado
Support type: Research Projects - Thematic Grants
FAPESP's process: 09/02217-1 - GLUT4 gene regulation by estrogen: role of receptors ER alfa and ER beta
Grantee:Raquel Saldanha Campello
Support type: Scholarships in Brazil - Doctorate