FGF21, not GCN2, influences bone morphology due to dietary protein restrictions
FGF21, not GCN2, influences bone morphology due to dietary protein restrictions
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DOI：
10.1016/j.bonr.2019.100241
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发表时间：
2019-12
期刊：
影响因子：
2.5
通讯作者：
M. McNulty;Brad A. Goupil;Diana C. Albarado;T. Castaño-Martínez;Thomas H. Ambrosi;Š. Puh;T. Schulz
中科院分区：
文献类型：
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作者：
M. McNulty;Brad A. Goupil;Diana C. Albarado;T. Castaño-Martínez;Thomas H. Ambrosi;Š. Puh;T. Schulz
研究背景限制蛋白质摄入可显著增加血浆成纤维细胞生长因子21（FGF 21）浓度，因此成为治疗肥胖和糖耐量异常的一种新方法。类似地，已知甲硫氨酸的饮食限制模拟能量和蛋白质限制的代谢作用，其中FGF 21作为所需机制。然而，膳食蛋白质已被证明是正常骨生长所必需的，尽管关于膳食蛋白质限制对骨重建的影响存在相互矛盾的证据。本研究的目的是评估饮食蛋白质和蛋氨酸限制对瘦小鼠和肥胖小鼠骨骼的影响，并阐明是否FGF 21和一般对照非去阻遏蛋白2（GCN 2）激酶，这是一种新的内分泌途径的一部分，涉及蛋白质限制的检测，方法成年野生型（WT）或Fgf 21 KO小鼠饲喂正常蛋白质（18 kcal%; CON）或低蛋白（4 kcal%; LP）饮食2或27周。此外，成年WT或Gcn 2KO小鼠喂食CON或LP饮食27周。将年轻的新西兰肥胖（NZO）小鼠置于高脂肪饮食（提供对照蛋白质（16 kcal%; CON）、高碳水化合物（LP/HC）或高脂肪（LP/HF）方案中的低水平蛋白质（4 kcal%））或高脂肪饮食（蛋白质，16 kcal%）（提供对照蛋氨酸（0.86%; CON-MR）或低水平蛋氨酸（0.17%; MR））长达9周。从这些小鼠的后肢长骨收集和评估与微计算机断层扫描（μCT）的变化，骨小梁和皮质结构和质量。结果在WT小鼠的27周LP饮食显着减少皮质骨，这种效果增强删除Fgf 21，但不是Gcn 2。这种骨减少在LP饮食2周后没有出现。此外，Fgf 21 KO小鼠的骨明显少于WT小鼠。在肥胖的NZO小鼠中，饮食蛋白质和蛋氨酸限制改变了骨结构。这些变化是由FGF 21介导的，由于蛋氨酸限制在胱氨酸的存在下，这并没有增加血浆FGF 21水平，并没有影响骨architecture.ConclusionsThis研究提供了直接的证据，减少骨以下长期的饮食蛋白质限制在小鼠模型中，似乎是由FGF 21介导的影响。
BackgroundDietary protein restriction is emerging as an alternative approach to treat obesity and glucose intolerance because it markedly increases plasma fibroblast growth factor 21 (FGF21) concentrations. Similarly, dietary restriction of methionine is known to mimic metabolic effects of energy and protein restriction with FGF21 as a required mechanism. However, dietary protein has been shown to be required for normal bone growth, though there is conflicting evidence as to the influence of dietary protein restriction on bone remodeling. The purpose of the current study was to evaluate the effect of dietary protein and methionine restriction on bone in lean and obese mice, and clarify whether FGF21 and general control nonderepressible 2 (GCN2) kinase, that are part of a novel endocrine pathway implicated in the detection of protein restriction, influence the effect of dietary protein restriction on bone.MethodsAdult wild-type (WT) orFgf21KO mice were fed a normal protein (18 kcal%; CON) or low protein (4 kcal%; LP) diet for 2 or 27 weeks. In addition, adult WT orGcn2KO mice were fed a CON or LP diet for 27 weeks. Young New Zealand obese (NZO) mice were placed on high-fat diets that provided protein at control (16 kcal%; CON), low levels (4 kcal%) in a high-carbohydrate (LP/HC) or high-fat (LP/HF) regimen, or on high-fat diets (protein, 16 kcal%) that provided methionine at control (0.86%; CON-MR) or low levels (0.17%; MR) for up to 9 weeks. Long bones from the hind limbs of these mice were collected and evaluated with micro-computed tomography (μCT) for changes in trabecular and cortical architecture and mass.ResultsIn WT mice the 27-week LP diet significantly reduced cortical bone, and this effect was enhanced by deletion ofFgf21but notGcn2. This decrease in bone did not appear after 2 weeks on the LP diet. In addition,Fgf21KO mice had significantly less bone than their WT counterparts. In obese NZO mice dietary protein and methionine restriction altered bone architecture. The changes were mediated by FGF21 due to methionine restriction in the presence of cystine, which did not increase plasma FGF21 levels and did not affect bone architecture.ConclusionsThis study provides direct evidence of a reduction in bone following long-term dietary protein restriction in a mouse model, effects that appear to be mediated by FGF21.