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

Autor(es)

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]

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo de Revisão
• Fonte: CURRENT TOPICS IN MEDICINAL CHEMISTRY; v. 12, n. 19, p. 2059-2069, OCT 2012.
• Citações Web of Science: 12

Resumo

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)

• Processo FAPESP: 09/02217-1 - Regulação da expressão do gene do GLUT4 pelo estrógeno: papel dos receptores ER alfa e ER beta
• Beneficiário: Raquel Saldanha Campello
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 07/50554-1 - Transportadores de glicose e Diabetes mellitus: contribuição ao conhecimento da regulação da glicemia e do desenvolvimento de complicações
• Beneficiário: Ubiratan Fabres Machado
• Modalidade de apoio: Auxílio à Pesquisa - Temático