Bornstein Sheila, Brown Sue A, Le Phuong T, Wang Xunde, DeMambro Victoria, Horowitz Mark C, MacDougald Ormond, Baron Roland, Lotinun Sutada, Karsenty Gerard, Wei Wei, Ferron Mathieu, Kovacs Christopher S, Clemmons David, Wan Yihong, Rosen Clifford J
Maine Medical Center Research Institute (S.B., P.T.L., V.D., C.J.R.), Scarborough, Maine 04074; Division of Endocrinology, University of Virginia (S.A.B.), Charlottesville, Virginia 22904; Division of Pharmacology (X.W., W.W., Y.W.), University of Texas Southwestern, Dallas, Texas 75390; Department of Orthopaedics and Rehabilitation (M.C.H.), Yale University School of Medicine, New Haven, Connecticut 06510; Metabolism, Endocrinology and Diabetes Division (O.M.), University of Michigan, Ann Arbor, Michigan 48105; Harvard Dental School (R.B., S.L.), Boston, Massachusetts 02115; Department of Genetics (G.K., M.F.), Columbia University College of Physicians and Surgeons, New York, New York 10032; Division of Endocrinology (C.S.K.), Memorial University, St. John's, Newfoundland, Canada A1B 3V6; and Division of Endocrinology (D.C.), University of North Carolina Chapel Hill, Chapel Hill, North Carolina 27599.
Endocrinology. 2014 Sep;155(9):3516-26. doi: 10.1210/en.2014-1083. Epub 2014 Jun 10.
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.
哺乳与身体成分和骨量的显著变化相关。已知全身和局部骨骼因子，如核因子κ-B受体活化因子配体（RANKL）、甲状旁腺激素相关蛋白（PTHrP）、降钙素和雌激素，在哺乳期间及之后调节骨重塑。成纤维细胞生长因子21（FGF-21）可能作为一种内分泌因子，通过诱导糖异生和脂肪酸氧化来调节哺乳期间的身体成分变化。在本研究中，我们假设哺乳期间的代谢变化部分归因于循环中FGF-21的增加，而这反过来又可能加剧骨质流失。我们纵向分析了C57BL/6J（B6）小鼠在哺乳期间（哺乳第7天和第21天）及正常哺乳后（哺乳后第21天）的身体成分。在哺乳第7天，骨面积密度下降了10%（P <.001），骨吸收增加（P <.0001），脂肪百分比下降了20%，能量消耗增加（P <.01），腹股沟脂肪库和已形成的棕色脂肪组织中类棕色脂肪生成的标志物受到抑制。在哺乳第7天，血清FGF-21较基线增加了2.4倍（P <.0001），肝脏FGF-21 mRNA增加了8倍（P <.03），未羧化骨钙素（Glu13 OCn）增加了2倍（P <.01），并且胰岛素敏感性增强。在哺乳第21天观察到骨面积密度总体恢复，而股骨小梁骨体积分数仍降低（P <.01）。由于B6哺乳小鼠在哺乳第7天FGF-21水平迅速升高，我们接下来检查了Fgf21基因缺失的哺乳小鼠。FGF-21（-/-）小鼠在整个哺乳期间小梁骨和皮质骨量均得以维持，并且幼崽生长正常。与哺乳对照小鼠相比，哺乳的FGF-21（-/-）小鼠骨形成增加，但骨吸收无变化。总之，除了钙调节激素的变化外，全身FGF-21在B6小鼠哺乳期间的骨骼重塑和身体成分变化中起作用。
