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

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

Author Campello, R. S. Google Scholar
Alves-Wagner, A. B. Google Scholar
Lucas, T. F. Autor UNIFESP Google Scholar
Mori, R. C. Google Scholar
Furuya, D. T. Google Scholar
Porto, Catarina Segreti Autor UNIFESP Google Scholar
Machado, U. F. Google Scholar
Institution Universidade de São Paulo (USP)
Universidade Federal de São Paulo (UNIFESP)
Abstract 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.
Keywords adipocyte
glucose uptake
NF-kappa B
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Grant number FAPESP: 2007/50554-1
FAPESP: 2009/02217-1
Date 2012-10-01
Published in Current Topics In Medicinal Chemistry. Sharjah: Bentham Science Publ Ltd, v. 12, n. 19, p. 2059-2069, 2012.
ISSN 1568-0266 (Sherpa/Romeo, impact factor)
Publisher Bentham Science Publ Ltd
Extent 2059-2069
Access rights Closed access
Type Review
Web of Science ID WOS:000313783700004

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