Activation of hepatic estrogen receptor-α increases energy expenditure by stimulating the production of fibroblast growth factor 21 in female mice.
Molecular Metabolism. 2019-04-01; 22: 62-70
DOI: 10.1016/j.molmet.2019.02.002
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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.
Copyright © 2019. Published by Elsevier GmbH.