FGF-21 and Skeletal Remodeling During and After Lactation in C57BL/6J Mice

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, and estrogen are known to regulate bone remodeling during and after 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. We longitudinally 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, we next 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.

Maternal Mineral and Bone Metabolism During Pregnancy, Lactation, and Post-Weaning Recovery

“…Another recent study found that FGF21 circulates at high levels in lactating mice (101). This is a counterregulatory factor that stimulates gluconeogenesis and fatty acid oxidation during substrate deficiency, and a member of a subfamily that includes FGF23 (724).…”

“…Bone turnover markers are increased during lactation, with bone resorption markers generally showing proportionately greater increases than in bone formation markers (35,101,330,477,478,580,956,994). These alterations in bone turnover markers can be prevented by treatment with a bisphosphonate, OPG, and high-dose estradiol treatment (37, 956).…”

“…The tibiae and femora show similar changes in trabecular bone, while cortical bone displays reductions in cortical thickness, cross-sectional area, and tissue mineral density, and an increase in cortical porosity and endosteal perimeter (35, 101,566,580). However, another microCT study from the same investigators found no significant change in cortical parameters in the femora except for an increase in tissue density (34), while a peripheral QCT (pQCT) study found that lactation increased tibial mid-shaft cortical width, area, periosteal circumference, and cross-sectional moment of inertia in frontal, sagittal, and torsional planes (772).…”

“…This is a counterregulatory factor that stimulates gluconeogenesis and fatty acid oxidation during substrate deficiency, and a member of a subfamily that includes FGF23 (724). Intriguingly, Fgf21 null mice do not resorb bone during lactation, as shown by microCT of the proximal tibiae, histomorphometric analysis of femora, and a lack of increase in bone resorptive markers (101).…”

Energy Excess, Glucose Utilization, and Skeletal Remodeling: New Insights

“…In states in which SNS tone is high (eg, cold exposure, FGF-21 excess), beige cells are found in the subcutaneous or inguinal depot. (42) On the other hand, bone mass is significantly reduced during high SNS tone, principally due to activation of the b2 receptor on osteoblasts. Activation of this receptor suppresses the key transcription factor, ATF4, while it enhances RANKL production.…”