17β-estradiol induces an interaction between adenosine monophosphate-activated protein kinase and the insulin signaling pathway in 3T3-L1 adipocytes

Estrogen (17 beta-estradiol) has been implicated in maintaining insulin sensitivity. It is thought to act predominantly through genomic pathways and regulate the expression of various genes via binding to estrogen receptors (ERs)-alpha and -beta. 17 beta-estradiol has been reported to simultaneously stimulate protein kinase B (Akt) and adenosine monophosphate-activated protein kinase (AMPK) in ex vivo skeletal muscle. Since data regarding the interaction between AMPK and the insulin receptor substrate-1 (IRS-1)/Akt pathway are controversial, the correlation between AMPK activation and insulin signaling remains unclear. In this study, we examined whether 17 beta-estradiol simultaneously stimulates the activation of AMPK and IRS-1/Akt in 3T3-L1 adipocytes as well as the 17 beta-estradiol-ER-induced interaction between the AMPK and IRS-1/Akt pathway in 3T3-L1 adipocytes not exposed to insulin. 17 beta-estradiol (10(-7) M) rapidly activated AMPK and IRS-1/Akt in 3T3-L1 adipocytes, while the ER-alpha/beta non-specific antagonist, ICI 182.780 (10 mu M), and the AMPK antagonist compound C (20 mu M) reversed the estrogen-induced activation of AMPK and tyrosine (Tyr)-IRS-1/Akt in these cells. Moreover, 17 beta-estradiol increased the expression of the peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC1 alpha), adiponectin, uncoupling protein 2 (UCP2) and glucose transporter 4 (GLUT4) genes 24 h after treatment, whereas the ER-alpha/beta non-specific antagonist, ICI 182.780 (10 mu M), and the AMPK antagonist compound C (20 mu M) reversed the estrogen-induced increase in the expression of these genes. These results indicate that 17 beta-estradiol activates AMPK through an ER and activates Akt through AMPK activation in 3T3-L1 adipocytes, despite the absence of insulin. Furthermore, 17 beta-estradiol regulates the expression of genes related to glucose metabolism through ER-AMPK activation in these cells.