McNulty Margaret A, Goupil Brad A, Albarado Diana C, Castaño-Martinez Teresa, Ambrosi Thomas H, Puh Spela, Schulz Tim J, Schürmann Annette, Morrison Christopher D, Laeger Thomas
Department of Anatomy, Cell Biology, & Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Department of Comparative Biomedical Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA 70803, USA.
Bone Rep. 2019 Dec 31;12:100241. doi: 10.1016/j.bonr.2019.100241. eCollection 2020 Jun.
Dietary 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.
Adult wild-type (WT) or KO 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 or KO 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.
In WT mice the 27-week LP diet significantly reduced cortical bone, and this effect was enhanced by deletion of but not . This decrease in bone did not appear after 2 weeks on the LP diet. In addition, KO 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.
This 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.
膳食蛋白质限制正成为治疗肥胖和葡萄糖不耐受的一种替代方法，因为它能显著提高血浆成纤维细胞生长因子21（FGF21）的浓度。同样，已知蛋氨酸的膳食限制可模拟能量和蛋白质限制的代谢效应，FGF21是其中的一个必要机制。然而，正常骨骼生长需要膳食蛋白质，尽管关于膳食蛋白质限制对骨重塑的影响存在相互矛盾的证据。本研究的目的是评估膳食蛋白质和蛋氨酸限制对瘦型和肥胖型小鼠骨骼的影响，并阐明FGF21和一般控制非抑制性2（GCN2）激酶（它们是参与检测蛋白质限制的一种新的内分泌途径的一部分）是否影响膳食蛋白质限制对骨骼的作用。
成年野生型（WT）或基因敲除小鼠分别喂食正常蛋白质（18千卡%；CON）或低蛋白质（4千卡%；LP）饮食2周或27周。此外，成年WT或基因敲除小鼠喂食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中，这些饮食以对照（16千卡%；CON）、高碳水化合物（LP/HC）或高脂肪（LP/HF）方案中的低水平（4千卡%）提供蛋白质，或者置于以对照（0.86%；CON-MR）或低水平（0.17%；MR）提供蛋氨酸的高脂肪饮食（蛋白质，16千卡%）中，持续9周。收集这些小鼠后肢的长骨，并用微型计算机断层扫描（μCT）评估小梁和皮质结构及质量的变化。
在WT小鼠中，27周的LP饮食显著降低了皮质骨，基因敲除可增强这种作用，而基因敲除则无此作用。LP饮食2周后未出现这种骨骼减少的情况。此外，基因敲除小鼠的骨骼明显少于其WT同窝小鼠。在肥胖的NZO小鼠中，膳食蛋白质和蛋氨酸限制改变了骨骼结构。这些变化是由FGF21介导的，原因是在存在胱氨酸的情况下蛋氨酸受到限制，胱氨酸不会增加血浆FGF21水平且不影响骨骼结构。
本研究提供了小鼠模型中长期膳食蛋白质限制后骨骼减少的直接证据，这种影响似乎是由FGF21介导的。
