Estrogen Improves Insulin Sensitivity and Suppresses Hepatic Glucose Production via the Transcription Factor Foxo1

Premenopausal women exhibit enhanced insulin sensitivity and reduced incidence of type 2 diabetes compared with age-matched men, but this advantage disappears after menopause with disrupted glucose homeostasis, in part, owing to a reduction in circulating 17β-estradiol (E₂). Fasting hyperglycemia, a feature of diabetes mellitus, is largely derived from dysregulation of hepatic glucose production (HGP), in which hyper-activated Foxo1 induces transcription of genes coding gluconeogenic enzymes. We investigated the E₂ action on the regulation of glucose hemostasis in male and ovariectomized (OVX) female of control and liver-specific Foxo1 knockout (L-F1KO) mice, and sought to understand the mechanism by which E₂ regulates gluconeogenesis via the interaction with liver Foxo1. E₂ subcutaneous implant led to decreased fasting blood glucose and improvement of insulin sensitivity in both male and OVX female mice in parallel with the suppression of gluconeogenesis and hepatic gluconeogenic gene expression, including glucose 6-phosphatase (G6pase) and phosphoenolpyruvate carboxykinase 1 (Pck1). Importantly, these effects of E₂ were only observed in control mice but disrupted in L-F1KO mice. Moreover, suppression of HGP and gluconeogenesis by E₂ only occurred in hepatocytes isolated from control mice and we confirmed that Foxo1 was required for the E₂ action on gluconeogenesis. E₂ suppressed Foxo1 via activation of ERα and phosphorylation of Akt, while inhibition of both ERα and Akt signaling abolished the effect of E₂ on gluconeogenesis. Collectively we demonstrated that the activation of ERα-Akt-Foxo1 signaling serves as an important mechanism of estrogen in control of glucose homeostasis. These results may help explain the gender difference in the incidence of type 2 diabetes and suggest an approach to target ERα to modulate glucose metabolism in diabetic patients.