Marrow Adipose Compartment Physiology in Caloric Restriction and Aging

热量限制和衰老中的骨髓脂肪室生理学

• 批准号: 10373992
• 负责人: Maya Shalev Styner
• 金额: $ 33.87万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-05 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373992
• 关键词: Adipocytes; Adipose tissue; Age; Aging; Anabolism; Anorexia; Biogenesis; Biomechanics; Body mass index; Bone Density; Bone Marrow; CD36 gene; CDKN2A gene; Caloric Restriction; Calories; Catabolic Process; Catabolism; Cell Lineage; Clinical; Data; Development; Exercise; Exhibits; Fatty Acids; Fatty acid glycerol esters; Gluconeogenesis; Glycogen; Health; Histologic; Inflammation; Inflammatory; Lead; Lipids; Lipolysis; Magnetic Resonance Imaging; Marrow; Measures; Mesenchymal Differentiation; Mesenchymal Stem Cells; Metabolic; Methods; Mitochondria; Modeling; Molecular Analysis; Mus; Osteoclasts; Osteogenesis; Osteoporotic; Oxides; Pathologic; Phenotype; Physiological; Physiology; Porosity; Positioning Attribute; Process; Reporter; Role; Serum; TNF gene; Techniques; Testing; Tissue Expansion; Western Blotting; aged; attenuation; biomechanical test; bone; bone health; bone loss; bone quality; bone turnover; exercise intervention; fracture risk; improved; innovation; metabolic phenotype; molecular phenotype; mouse model; osteoclastogenesis; overexpression; oxidation; response; senescence; skeletal; targeted treatment; transcriptome sequencing; translocase; uptake

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.

抽象的 尽管骨髓脂肪组织与低骨密度和增加骨折风险有关， (MAT) 对 MAT 为运动引起的骨合成代谢提供能量仍知之甚少。 在热量限制和衰老导致的骨质疏松状态下，MAT 的作用可能是这样的。 我们的数据显示 MAT 的 CR 增加与骨转换率和数量的降低同时发生。 运动时，CR-MAT 降低，周转率增加，并且发生骨质流失（脂肪标记物 CD36）。 CR 骨中酸的摄取增加，同时脂肪酸动员标志物减少 和 β-氧化，表明 CR-MAT 的脂肪分解能力降低。 在我们的两种衰老模型中，由于脂肪分解的代谢能力降低，可能无法实现。 MAT 增加；此外，破骨细胞位于老年小鼠骨骼和骨骼中 因此，吸收、炎症和线粒体生物发生的标志物增加。 在热量充足、非衰老状态下，运动会消耗 MAT 以支持 骨合成代谢；然而，在 CR 和可能的衰老过程中，MAT 的运动利用可支持骨骼 在 SA1 中，我们将询问 MAT 和骨骼在热量限制期间对运动有何反应。 在 SA2 中，我们确定老化过程中 MAT 和骨骼对运动的反应。 对 MAT 进行量化、定位和代谢表型分析的创新技术。 将用于识别新分化的骨髓脂肪细胞并表征细胞 水平-MAT是否因脂质摄取或CR中的MSC谱系转换而增加， 除了生理老化之外，还将使用早衰小鼠模型来测试骨骼和 MAT 结合体积 MAT 测量、脂肪细胞谱系追踪、组织学。 MAT、代谢能力测量以及骨微结构的分子分析 通过 µCT、生物力学测试和动态组织形态计量学，我们可以回答 关于 MAT 在 CR 和衰老过程中的代谢功能的基本问题， 及其与骨骼健康的关系。