Estrogen Improves Insulin Sensitivity and Suppresses Gluconeogenesis via the Transcription Factor Foxo1

Abstract

Premenopausal women exhibit enhanced insulin sensitivity and reduced incidence of type 2 diabetes (T2D) compared with age-matched men, but this advantage disappears after menopause with disrupted glucose homeostasis, in part owing to a reduction in circulating 17b-estradiol (E 2 ). Fasting hyperglycemia is a hallmark of T2D derived largely from dysregulation of hepatic glucose production (HGP), in which Foxo1 plays a central role in the regulation of gluconeogenesis. Here, we investigated the action of E 2 on glucose homeostasis in male and ovariectomized (OVX) female control and liverspecific Foxo1 knockout (L-F1KO) mice and sought to understand the mechanism by which E 2 regulates gluconeogenesis via an interaction with hepatic Foxo1. In both male and OVX female control mice, subcutaneous E 2 implant improved insulin sensitivity and suppressed gluconeogenesis; however, these effects of E 2 were abolished in L-F1KO mice of both sexes. In our use of mouse primary hepatocytes, E 2 suppressed HGP and gluconeogenesis in hepatocytes from control mice but failed in hepatocytes from L-F1KO mice, suggesting that Foxo1 is required for E 2 action on the suppression of gluconeogenesis. We further demonstrated that E 2 suppresses hepatic gluconeogenesis through activation of estrogen receptor (ER)a-phosphoinositide 3-kinase-Akt-Foxo1 signaling, which can be independent of insulin receptor substrates 1 and 2 (Irs1 and Irs2), revealing an important mechanism for E 2 in the regulation of glucose homeostasis. These results may help explain why premenopausal women have lower incidence of T2D than age-matched men and suggest that targeting ERa can be a potential approach to modulate glucose metabolism and prevent diabetes.

Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α

“…As alluded to previously, evidence in the literature indicates the binding affinity of 17β-E2 for ERs is dramatically greater than 17α-E2, which has been confirmed with competitive binding assays [32][33][34][35]. In males, very few studies have evaluated the role of ERα in metabolism, although a few recent reports have suggested that ERα plays tissue-specific roles, particularly in the liver, by regulating male metabolic homeostasis [38][39][40][41]55]. These studies, coupled with our current findings, led us to speculate that 17α-E2 may be signaling through ERα in the liver to reverse metabolic disease and potentially extend healthspan and/or lifespan in males.…”

“…For instance, Allard and colleagues recently demonstrated that genomic actions of ERα regulate systemic glucose homeostasis in mice of both sexes and insulin production and release in males [38]. Other studies have also determined that hepatic steatosis and insulin sensitivity, and therefore the control of gluconeogenesis, are regulated through FOXO1 in an ERα-dependent manner in male mice [39]. Furthermore, liver-specific deletion of ERα was sufficient to abrogate similar estrogen-mediated metabolic benefits [40,41].…”

GDM progenies exhibit sex disparity in metabolism after respective therapies of insulin, glibenclamide and metformin in dams during pregnancy

“…improves insulin sensitivity and suppresses hepatic gluconeogenesis through inhibition of Foxo1 via activation of ERα-PI3K-Akt signaling by investigating the action of E2 on glucose homeostasis in male and ovariectomized female control and liver-speci c Foxo1 knockout mice 27 . It was reported that estrogen receptor a (ERa) regulated β-cell formation during pancreatic development 28 .…”

Insulin Resistance and Endometrial Cancer: Emerging Role for microRNA

“…Research on ER-positive breast cancer (cell line MCF-7 xenografts) demonstrated that tamoxifen, a selective ER modulator, effectively inhibits classical ER-dependent transcription, including the transcription of IGF1R gene product [92]. In vivo studies have shown that E2 improves insulin sensitivity and glucose tolerance via activation of ERα/PI3K/Akt signaling [93,94]. However, E2 has been demonstrated to inhibit the in vitro binding of insulin to INSR by binding to both insulin and its receptor instead, an observation strongly suggesting the ability of E2 to induce IR either directly or indirectly [95].…”