FGF-21 and skeletal remodeling during and after lactation in C57BL/6J mice

Sheila Bornstein, Sue A. Brown, Phuong T. Le, Xunde Wang, Victoria DeMambro, Mark C. Horowitz, Ormond MacDougald, Roland Baron, Sutada Lotinun, Gerard Karsenty, Wei Wei, Mathieu Ferron, Christopher S. Kovacs, David Clemmons, Yihong Wan, Clifford J. Rosen

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Lactation is associated with significant alterations in both body composition and bone mass. Systemic and local skeletal factors such as receptor activator of nuclear factor κ-B ligand (RANKL), PTHrP, calcitonin,andestrogen areknownto regulateboneremodeling duringandafter lactation. Fibroblast growth factor 21 (FGF-21) may function as an endocrine factor to regulate body composition changes during lactation by inducing gluconeogenesis and fatty acid oxidation. In this study, we hypothesized that the metabolic changes during lactation were due in part to increased circulating FGF-21, which in turn could accentuate bone loss.Welongitudinally characterized body composition in C57BL/6J (B6) mice during (day 7 and day 21 of lactation) and after normal lactation (day 21 postlactation). At day 7 of lactation, areal bone density declined by 10% (P <.001), bone resorption increased (P<.0001), percent fat decreased by 20%, energy expenditure increased (P<.01), and markers of brown-like adipogenesis were suppressed in the inguinal depot and in preformed brown adipose tissue. At day 7 of lactation there was a 2.4-fold increase in serum FGF-21 vs baseline (P <.0001), a 8-fold increase in hepatic FGF-21 mRNA (P <.03), a 2-fold increase in undercarboxylated osteocalcin (Glu13 OCn) (P<.01), and enhanced insulin sensitivity. Recovery of total areal bone density was noted at day 21 of lactation, whereas the femoral trabecular bone volume fraction was still reduced (P <.01). Because FGF-21 levels rose rapidly at day 7 of lactation in B6 lactating mice,wenext examined lactating mice with a deletion in the Fgf21 gene. Trabecular and cortical bone masses were maintained throughout lactation in FGF-21-/-mice, and pup growth was normal. Compared with lactating control mice, lactating FGF-21-/-mice exhibited an increase in bone formation, but no change in bone resorption. In conclusion, in addition to changes in calciotropic hormones, systemic FGF-21 plays a role in skeletal remodeling and changes in body composition during lactation in B6 mice. Copyright

Original languageEnglish (US)
Pages (from-to)3516-3526
Number of pages11
JournalEndocrinology
Volume155
Issue number9
DOIs
StatePublished - Sep 1 2014

ASJC Scopus subject areas

  • Endocrinology

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    Bornstein, S., Brown, S. A., Le, P. T., Wang, X., DeMambro, V., Horowitz, M. C., MacDougald, O., Baron, R., Lotinun, S., Karsenty, G., Wei, W., Ferron, M., Kovacs, C. S., Clemmons, D., Wan, Y., & Rosen, C. J. (2014). FGF-21 and skeletal remodeling during and after lactation in C57BL/6J mice. Endocrinology, 155(9), 3516-3526. https://doi.org/10.1210/en.2014-1083