Metabolic benefits of 17α-estradiol in liver are partially mediated by ERβ in male mice

Abstract

Metabolic dysfunction underlies several chronic diseases. Dietary interventions can reverse metabolic declines and slow aging but remaining compliant is difficult. 17α-estradiol (17α-E2) treatment improves metabolic parameters and slows aging in male mice without inducing significant feminization. We recently reported that estrogen receptor α is required for the majority of 17α-E2-mediated benefits in male mice, but that 17α-E2 also attenuates fibrogenesis in liver, which is regulated by estrogen receptor β (ERβ)-expressing hepatic stellate cells (HSC). The current studies sought to determine if 17α-E2-mediated benefits on systemic and hepatic metabolism are ERβ-dependent. We found that 17α-E2 treatment reversed obesity and related systemic metabolic sequela in both male and female mice, but this was partially blocked in female, but not male, ERβKO mice. ERβ ablation in male mice attenuated 17α-E2-mediated benefits on hepatic stearoyl-coenyzme A desaturase 1 (SCD1) and transforming growth factor β1 (TGF-β1) production, which play critical roles in HSC activation and liver fibrosis. We also found that 17α-E2 treatment suppresses SCD1 production in cultured hepatocytes and hepatic stellate cells, indicating that 17α-E2 directly signals in both cell-types to suppress drivers of steatosis and fibrosis. We conclude that ERβ partially controls 17α-E2-mediated benefits on systemic metabolic regulation in female, but not male, mice, and that 17α-E2 likely signals through ERβ in HSCs to attenuate pro-fibrotic mechanisms.

17α-estradiol Alleviates High-Fat Diet-Induced Inflammatory and Metabolic Dysfunction in Skeletal Muscle of Male and Female Mice

“…As shown elsewhere, 31 body mass and fat mass were found to have a main effect of time and treatment for male mice, and a main effect of treatment in female mice. For fat-free mass, there was a main effect of treatment for male mice, and a main effect of time in the female mice.…”

“…These animals were part of a larger study published elsewhere. 31 We reproduce body and fat mass from the previous publication because they inform our analyses. We bred experimental C57BL/6 mice in-house, group-housed by sex and fed standard chow until 12 weeks of age.…”

“…Female mice with intact ovarian function do not respond to 17α-E2. [24][25][26][27][28][29][30] However, female mice with metabolic dysfunction 31 or that undergo ovariectomy do gain metabolic benefits from 17α-E2. 32 Even so, chronic administration of 17α-E2 does not protect ovariectomized female mice against age-related metabolic dysfunction.…”