Diabetes Discovery Research and Sex-Based Medicine Laboratory, Department of Medicine, Section of Endocrinology and Metabolism, Tulane University Health Sciences Center, School of Medicine, USA.
LACESP, INSERM U1018, Université Paris-Sud, UVSQ, Université Paris-Saclay, Gustave Roussy, Villejuif Cedex, F-94805, France.
Mol Metab. 2019 Apr;22:62-70. doi: 10.1016/j.molmet.2019.02.002. Epub 2019 Feb 14.
The endogenous estrogen 17β-estradiol (E2) promotes metabolic homeostasis in premenopausal women. In a mouse model of post-menopausal metabolic syndrome, we reported that estrogens increased energy expenditure, thus preventing estrogen deficiency-induced adiposity. Estrogens' prevention of fat accumulation was associated with increased serum concentrations of fibroblast growth factor 21 (FGF21), suggesting that FGF21 participates in estrogens' promotion of energy expenditure.
We studied the effect of E2 on FGF21 production and the role of FGF21 in E2 stimulation of energy expenditure and prevention of adiposity, using female estrogen receptor (ER)- and FGF21-deficient mice fed a normal chow and a cohort of ovariectomized women from the French E3N prospective cohort study.
E2 acting on the hepatocyte ERα increases hepatic expression and production of FGF21 in female mice. In vivo activation of ERα increases the transcription of Fgf21 via an estrogen response element outside the promoter of Fgf21. Treatment with E2 increases oxygen consumption and energy expenditure and prevents whole body fat accumulation in ovariectomized female WT mice. The effect of E2 on energy expenditure is not observed in FGF21-deficient mice. While E2 treatment still prevents fat accumulation in FGF21-deficient mice, this effect is decreased compared to WT mice. In an observational cohort of ovariectomized women, E2 treatment was associated with lower serum FGF21 concentrations, which may reflect a healthier metabolic profile.
In female mice, E2 action on the hepatocyte ERα increases Fgf21 transcription and FGF21 production, thus promoting energy expenditure and partially decreasing fat accumulation.
内源性雌激素 17β-雌二醇（E2）促进绝经前女性的代谢稳态。在绝经后代谢综合征的小鼠模型中，我们报道雌激素增加了能量消耗，从而防止了雌激素缺乏引起的肥胖。雌激素防止脂肪堆积与血清成纤维细胞生长因子 21（FGF21）浓度增加有关，表明 FGF21 参与了雌激素对能量消耗的促进作用。
我们研究了 E2 对 FGF21 产生的影响以及 FGF21 在 E2 刺激能量消耗和防止肥胖中的作用，使用正常饲料喂养的雌性雌激素受体（ER）和 FGF21 缺陷小鼠以及来自法国 E3N 前瞻性队列研究的一组卵巢切除妇女。
E2 作用于肝细胞 ERα 增加了雌性小鼠肝脏中 FGF21 的表达和产生。在体内，通过 Fgf21 启动子外的雌激素反应元件，激活 ERα 增加了 Fgf21 的转录。E2 处理增加了耗氧量和能量消耗，并防止了卵巢切除 WT 雌性小鼠的全身脂肪积累。E2 对能量消耗的作用在 FGF21 缺陷小鼠中观察不到。虽然 E2 处理仍能防止 FGF21 缺陷小鼠的脂肪积累，但与 WT 小鼠相比，这种作用降低了。在卵巢切除妇女的观察性队列中，E2 治疗与血清 FGF21 浓度降低有关，这可能反映了更健康的代谢特征。
在雌性小鼠中，E2 对肝细胞 ERα 的作用增加了 Fgf21 的转录和产生，从而促进了能量消耗，并部分减少了脂肪积累。
