Marrow Adipose Compartment Physiology in Caloric Restriction and Aging

摘要 尽管它与低骨密度和增加骨折风险有关，但骨髓脂肪组织 (MAT)仍然知之甚少。MAT为运动性骨合成代谢提供能量 卡路里充足的状态。在骨质疏松的卡路里限制和衰老状态中，MAT的作用可能 不同。我们的数据显示，在骨转换和骨数量减少的同时，MAT增加了CR。使用 运动后，CR-MAT减少，周转率增加，出现骨质流失。CD36，脂肪的标志物 随着脂肪酸动员标志物的减少，CR骨中的酸摄取增加 和β氧化，表明CR-MAT的脂解能力降低。因此，CR-MAT仓库 由于脂肪分解代谢能力降低，可能无法接触到。在我们的两个衰老模型中， MAT增加；此外，在老化的小鼠骨骼和骨骼中，破骨细胞定位于MAT 吸收、炎症和线粒体生物发生的标志物增加。因此，我们 假设在卡路里充足的非衰老条件下，运动会消耗垫子来支持 骨合成代谢；然而，在CR和可能的衰老中，运动利用垫子支持骨骼 分解代谢。在SA1中，我们将询问在限制卡路里的过程中，垫和骨骼对运动的反应。 在SA2中，我们确定了垫和骨骼在衰老过程中对运动的反应。本提案使用 用于量化、定位和代谢表型垫的创新技术。一只记者老鼠 将用于鉴定新分化的骨髓脂肪细胞，并在细胞内 水平-在CR中，MAT是由于脂质摄取还是由于MSC谱系转换而增加。在SA2中， 除了生理老化外，还将使用一种程序性小鼠模型来测试骨骼和垫子 对运动的反应。结合体积垫测量，脂肪细胞谱系追踪，组织学 和MAT的分子分析、新陈代谢能力测量以及骨骼微结构 通过µCT、生物力学测试和动态组织形态测量，我们可以回答 关于MAT在CR和老化环境中的代谢功能的基本问题， 以及它与骨骼健康的关系。

ABSTRACT Despite its association with low bone density and increased fracture risk, marrow adipose tissue (MAT) remains poorly understood. MAT provides energy for exercise-induced bone anabolism in a calorie-replete state. In the osteoporotic states of caloric restriction and aging, MAT's role may differ. Our data shows MAT increases in CR in parallel to low bone-turnover and quantity. With exercise, CR-MAT decreases, turnover increases, and bone loss occurs. CD36, a marker for fatty acid uptake, increased in CR-bone, along with a diminution in markers of fatty acid mobilization and β-oxidation, suggesting a decreased lipolytic capacity in CR-MAT. Thus, the CR-MAT depot may be inaccessible, due to reduced metabolic capacity for lipolysis. In our two models of aging, MAT increased; also, osteoclasts localized to MAT in aged mouse bones and bones showed increased markers of resorption, inflammation, and mitochondrial biogenesis. We thus hypothesize that in a calorie replete, non-aged condition, exercise depletes MAT in support of bone anabolism; however, in CR, and possibly aging, exercise utilization of MAT supports bone catabolism. In SA1, we will ask how MAT and bone respond to exercise during calorie restriction. In SA2 we determine how MAT and bone respond to exercise during aging. This proposal uses innovative techniques to quantify, localize and metabolically phenotype MAT. A reporter mouse will be used to identify newly differentiated marrow adipocytes and characterize-at the cellular level-whether MAT is increased due to lipid uptake or due to MSC lineage switch in CR. IN SA2, a progeroid mouse model will be used in addition to physiologic aging to test the bone and MAT response to exercise. Combining a volumetric MAT measure, adipocyte lineage tracing, histologic and molecular analyses of MAT, metabolic capacity measures, as well as bone microarchitecture via µCT, biomechanical testing and dynamic histomorphometry, positions us to answer fundamental questions as to the metabolic function of MAT in the setting of both CR and aging, and its relationship to bone health.