Estrogen augments glucose transporter and IGF1 expression in primate cerebral cortex

Estrogen has many positive effects on neural tissue in experimental model systems, including stimulation of neurite growth and neurotransmitter synthesis and protection against diverse types of neural injury. In humans, estrogen treatment is reputed to protect against Alzheimer's disease. To investigate potential mediators of estrogen's action and determine whether selective estrogen receptor modulators (SERMs) such as tamoxifen have estrogen-like effects in the primate brain, we evaluated the expression of glucose transporters and insulin-like growth factor 1 (IGF1) and its receptor in the frontal cortex of ovariectomized rhesus monkeys. We treated one group for 3 days with vehicle, another with 17 beta estradiol (E2), and a third with tamoxifen. The expression of facilitative glucose transporters (Gluts) 1, 3, and 4 was investigated using in situ hybridization, immunohistochemistry, and immunoblot analysis. Gluts 3 and 4 were concentrated in cortical neurons and Glut1 in capillaries and glial cells. E2 treatment induced two- to fourfold increases in Glut3 and Glut4 mRNA levels and lesser but significant increases in Glut3 and 4 protein levels. E2 treatment induced an approximately 70% increase in parenchymal Glut1 mRNA levels, but did not appreciably affect vascular Glut1 gene expression. IGF1 and IGF1 receptor mRNAs were concentrated in cortical neurons in a distribution similar to Gluts 3 and 4. IGF1 mRNA levels were significantly increased in E2-treated animals but IGF1 receptor mRNA levels were not altered by hormone treatment. Tamoxifen increased cerebral cortical Glut3 and 4 mRNA levels, but did not affect Glut1, IGF1, or IGF1 receptor expression. This study provides novel data showing that Gluts 3 and 4 and IGF1 are coexpressed by primate cerebral cortical neurons, where their expression is enhanced by estrogen. These findings suggest that up-regulation of glucose transporter and IGF1 expression may contribute to estrogen's salutary effects on neural tissue. Tamoxifen, an antiestrogen at the breast, is shown to have estrogen-like effects on higher brain centers in the monkey, suggesting that some SERMs may share estrogen's neuroprotective potential for menopausal women.