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

Abstract

Estrogen (17β-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)-α and -β. 17β-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 17β-estradiol simultaneously stimulates the activation of AMPK and IRS-1/Akt in 3T3-L1 adipocytes as well as the 17β-estradiol-ER-induced interaction between the AMPK and IRS-1/Akt pathway in 3T3-L1 adipocytes not exposed to insulin. 17β-estradiol (10⁻⁷ M) rapidly activated AMPK and IRS-1/Akt in 3T3-L1 adipocytes, while the ER-α/β non-specific antagonist, ICI 182.780 (10 µM), and the AMPK antagonist compound C (20 µM) reversed the estrogen-induced activation of AMPK and tyrosine (Tyr)-IRS-1/Akt in these cells. Moreover, 17β-estradiol increased the expression of the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), adiponectin, uncoupling protein 2 (UCP2) and glucose transporter 4 (GLUT4) genes 24 h after treatment, whereas the ER-α/β non-specific antagonist, ICI 182.780 (10 µM), and the AMPK antagonist compound C (20 µM) reversed the estrogen-induced increase in the expression of these genes. These results indicate that 17β-estradiol activates AMPK through an ER and activates Akt through AMPK activation in 3T3-L1 adipocytes, despite the absence of insulin. Furthermore, 17β-estradiol regulates the expression of genes related to glucose metabolism through ER-AMPK activation in these cells.

Estrogen deprivation and excess energy supply accelerate 7,12-dimethylbenz(a)anthracene-induced mammary tumor growth in C3H/HeN mice

“…In this study, we found that the OVX+HD group showed higher AMPK expression, which may have led to down-regulated expression of mTOR, thereby suppressing tumor growth. Estrogen has been implicated in maintenance of insulin sensitivity [ 62 ], and stimulated AMPK phosphorylation by17β-estradiol through estrogen receptor α in 3T3-L1 adipocytes has also been reported [ 63 ]. In addition, injections of estradiol resulted in activation of AMPK in ovariectomized mice [ 64 ].…”

The role of sex steroids in white adipose tissue adipocyte function

“…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). It also has been shown that E2 activates adenosine monophosphate-activated protein kinase (AMPK) through ER and activates protein kinase B (AKT) via AMPK even in the absence of insulin in cell culture (Kim et al 2012).…”

Skeletal muscle AMP-activated protein kinase γ1H151R overexpression enhances whole body energy homeostasis and insulin sensitivity

“…Moreover, in obese mouse models, estrogen signaling improves hepatic insulin sensitivity (45). Estrogen increases AMPK and Akt phosphorylation in C 2 C 12 myotubes (14) as well as 3T3-L1 adipocytes (23), suggesting direct sex hormone effects on AMPK signaling. Importantly, our hyperinsulinemic euglycemic clamp studies reveal that whole body glucose utilization is increased in both female and male AMPK␥1 H151R transgenic mice, supporting a role for AMPK activation to enhance insulin sensitivity and whole body metabolism.…”