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

Camille Allard, Fabrice Bonnet, Beibei Xu, Laurel Coons, Diana Albarado, Cristal Hill, Guy Fagherazzi, Kenneth S. Korach, Ellis R. Levin, John Lefante, Christopher Morrison, Franck Mauvais-Jarvis

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3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)62-70
Number of pages9
JournalMolecular Metabolism
Volume22
DOIs
StatePublished - Apr 2019

Bibliographical note

Funding Information:
This work was supported by grants from the National Institutes of Health (NIH, R01 DK074970 , and DK107444 ), a Department of Veterans Affairs Merit Review Award (# BX003725 ), and the Price-Goldsmith Endowed Chair at Tulane University School of Medicine to FMJ. C.A. was supported by American Diabetes Association Post-Doctoral Fellowship ( 1-16-PDF-004 ). CDM was supported by NIH R01DK105032 and CMH was supported by F32 DK11513 . JL was supported in part by 1 U54 GM104940 from the National Institute of General Medical Sciences of the NIH, which funds the Louisiana Clinical and Translational Science Center . This project/work used facilities within the Pennington Biomedical Animal Metabolism & Behavior Core that are supported in part by NIH COBRE ( P30GM118430 ) and NORC ( P30DK072476 ) center grants.

Funding Information:
This work was supported by grants from the National Institutes of Health (NIH, R01 DK074970, and DK107444), a Department of Veterans Affairs Merit Review Award (#BX003725), and the Price-Goldsmith Endowed Chair at Tulane University School of Medicine to FMJ. C.A. was supported by American Diabetes Association Post-Doctoral Fellowship (1-16-PDF-004). CDM was supported by NIH R01DK105032 and CMH was supported by F32 DK11513. JL was supported in part by 1 U54 GM104940 from the National Institute of General Medical Sciences of the NIH, which funds the Louisiana Clinical and Translational Science Center. This project/work used facilities within the Pennington Biomedical Animal Metabolism & Behavior Core that are supported in part by NIH COBRE (P30GM118430) and NORC (P30DK072476) center grants.

Publisher Copyright:
© 2019

Keywords

  • ERα
  • Estrogen
  • FGF21
  • Menopause
  • Metabolic syndrome
  • Obesity

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