Effects of estradiol and genistein on the insulin signaling pathway in the cerebral cortex of aged female rats

• An age-related decline was found in p-IRS1tyr612–p85α and ERα46–p85α interactions.
• Aging impaired GLUT4 translocation to the plasma membrane.
• ERα67 and ERα46 showed different interaction degree with IRS1 and p85α.
• Both estradiol and genistein stimulate AKT phosphorylation in aged rats.
• Only estradiol enhanced GLUT4 translocation to plasma membrane in aged rats.

Menopause leads to a decrease in estrogen production that increases central insulin resistance, contributing to the development of neurodegenerative diseases. We have evaluated the influence of aging and estradiol or genistein treatments on some key stages of the insulin signaling pathway in the cerebral cortex. Young and aged female Wistar rats were ovariectomized and treated acutely with 17β-estradiol (1.4 μg/kg body weight), two doses of genistein (10 or 40 mg/kg body weight), or vehicle. The cortical expression of several key insulin signaling pathway components was analyzed by western blotting. Our results showed an age-related deterioration in the interactions between the regulatory subunit of phosphatidylinositol 3-kinase (p85α) and the activated form of insulin receptor substrate 1 (p-IRS1tyr612), as well as between p85α and the 46 kDa isoform of the estrogen receptor α (ERα46). Moreover, aging also decreased the translocation of glucose transporter-4 (GLUT4) to the plasma membrane. 17β-Estradiol but not genistein reduced the negative impact of aging on central insulin sensitivity by favoring this GLUT4 translocation, and therefore could be neuroprotective against the associated neurodegenerative diseases. However, protein kinase B (Akt) activation by genistein suggests that other possible mechanisms are involved in the neuroprotective effects of this phytoestrogen during the aging process.