Activation of hepatic estrogen receptor-α increases energy expenditure by stimulating the production of fibroblast growth factor 21 in female mice

Authors

Camille Allard, 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.
Fabrice Bonnet, LACESP, INSERM U1018, Université Paris-Sud, UVSQ, Université Paris-Saclay, Gustave Roussy, Villejuif Cedex, F-94805, France.
Beibei Xu, 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.
Laurel Coons, Receptor Biology Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, NC 27709, USA.
Diana Albarado, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70803, USA.
Cristal Hill, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70803, USA.
Guy Fagherazzi, LACESP, INSERM U1018, Université Paris-Sud, UVSQ, Université Paris-Saclay, Gustave Roussy, Villejuif Cedex, F-94805, France.
Kenneth S. Korach

Document Type

Article

Publication Date

4-1-2019

Abstract

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: In female mice, E2 action on the hepatocyte ERα increases Fgf21 transcription and FGF21 production, thus promoting energy expenditure and partially decreasing fat accumulation.

Publication Source (Journal or Book title)

Molecular metabolism

First Page

62

Last Page

70

Recommended Citation

Allard, C., Bonnet, F., Xu, B., Coons, L., Albarado, D., Hill, C., Fagherazzi, G., & Korach, K. S. (2019). Activation of hepatic estrogen receptor-α increases energy expenditure by stimulating the production of fibroblast growth factor 21 in female mice. Molecular metabolism, 22, 62-70. https://doi.org/10.1016/j.molmet.2019.02.002