Estrogen Receptor .ALPHA. Regulates Insulin Sensitivity through IRS-1 Tyrosine Phosphorylation in Mature 3T3-L1 Adipocytes

Abstract

Abstract. There are many clinical and experimental reports demonstrating that estrogens and insulin interact when affecting their target organs. Estrogen receptors consist of two isoforms, estrogen receptors-alpha (ER-α) and -beta (ER-β), but their roles in insulin-induced glucose uptake in mature adipose tissue have yet to be clarified. To evaluate the roles of ER-α, expressed predominantly in adipocytes, we have investigated the effects of estradiol (E2), an ER-α selective agonist (PPT), and its selective antagonist (MPP) on glucose uptake and insulin action in 3T3-L1 adipocytes. 3T3-L1 adipocytes were exposed to E2 or PPT and/or MPP at different concentrations. The cells were then subjected to 2-deoxy-D-glucose transport assay, western blot analysis, or RT-PCR analysis. Treatment of these cells with E2 or PPT resulted in biphasic effects on glucose transport, that is high (10 -5 M or 3 × 10 -6 M each) and low (10 -8 M) doses produced inhibition and stimulation, respectively. The favorable effect observed at 10 -8 M of E2 was diminished by treatment with MPP. Western bolt analysis revealed that these effects of E2, PPT and MPP paralleled the level of IRS-1 tyrosine phosphorylation. However, IRS-1 serine phosphorylation, suppressor of cytokine signaling (SOCS)-1,-2,-3 and protein tyrosine phosphatase 1B (PTP1B) expression did not change compaired to control subjects. Our data clearly show that ER-α contributes to insulin stimulated glucose uptake through regulation of the tyrosine phosphorylation of IRS-1 protein.

Effects of 17β-estradiol and progesterone on the production of adipokines in differentiating 3T3-L1 adipocytes: Role of Rho-kinase

“…Interestingly, concomitant application of Y-27632 reversed this action, implicating that Rho-kinase may mediate the production /release of resistin by estrogen in any way. Estrogens and the activators of Rho/ROCK signaling may provoke insulin resistance through diverse cellular events including the inhibition of insulin signaling [17,[27][28][29]. Taken together, we could postulate that one of the reasons of 17b-estradiol-induced insulin resistance might be resulted from the increase in resistin but decrease in adiponectin levels, which requires further confirmation by in vivo studies.…”

Loss of Estrogen Receptor α Signaling Leads to Insulin Resistance and Obesity in Young and Adult Female Mice

“…In ovariectomized female rats, glucose intolerance induced by high-fat diet is associated with decreased expression of ER ␣ and glucose transporter type 4 (GLUT4) in adipose tissue but not in skeletal muscle, in concert with activation of pro-inflammatory molecules (c-jun NH 2 -terminal kinase and inhibitor of B kinase ␤ ), suggesting an impact of impaired glucose homeostasis on ER ␣ expression in adipose tissue [21] . Activation of ER ␣ in 3T3-L1 adipose cells improves insulin-stimulated glucose uptake along with increased insulin signaling as evaluated by tyrosine (P) of IRS-1 [22] .…”

The role of sex steroids in white adipose tissue adipocyte function

“…E2 modulates insulin signaling via ESR1 and stimulates the uptake of glucose into adipocytes via regulation of the tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) protein (Muraki et al 2006). However, high concentrations of E2 (10 −5 M) inhibited insulin signaling in adipocytes via modulation of IRS-1 phosphorylation at Ser 307 through a c-Jun NH 2 terminal kinase-dependent pathway (Nagira et al 2006).…”