Regulation of SLC2A4 expression by 17b estradiol: effects of estrogen receptors interaction with PPARgamma and NF-kB

Abstract

Type 2 diabetes mellitus (T2DM) 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. Recent studies have proposed that estradiol (E2) is able to modulate Slc2a4 expression, through its nuclear receptors, the estrogen receptors ESR1/ESR2. It is known that ESRs can interact with the transcription factors Nuclear Factor-ºB (NF-ºB) and peroxisome proliferator-activated receptor gamma (PPARgamma), two proteins are also implicated in the regulation of Slc2a4 expression. However, the effects of the interaction between ESRs, NF-ºB and PPARgamma on Slc2a4 gene expression have not been investigated so far. The present project therefore aims to investigate the participation of the transcription factors PPARgamma and NF-ºB in the modulation of Slc2a4 expression by ESRs. For this, 3T3-L1 adipocytes will be treated with 17² Estradiol and/or ESRs selective agonists and antagonists for 24 hours for the assessment of interaction between ESRs/NF-ºB and ESRs/PPARgamma. Additionally, Slc2a4 transcriptional regulation will be analyzed, in order to verify the effects of the ESRs/NF-ºB and ESRs/PPARgamma interactions on Slc2a4 expression. The results are expected to elucidate the molecular mechanism involved in Slc2a4 regulation by E2 as well as define the ESRs-nuclear proteins interaction profiling, which may be useful tool for new therapeutic approaches for T2DM treatment. (AU)