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: 9908052
• 负责人: Maya Shalev Styner
• 金额: $ 34.21万
• 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/9908052
• 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; 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.

摘要 尽管骨髓脂肪组织与低骨密度和骨折风险增加有关， (MAT)仍然知之甚少。MAT为运动诱导的骨愈合提供能量 一个卡路里充足的状态。在热量限制和衰老的病态状态下，MAT的作用可能 不同。我们的数据显示，CR中MAT的增加与低骨转换和数量平行。与 运动，CR-MAT降低，周转增加，骨丢失发生。CD 36，脂肪的标志物 酸摄取，CR-骨增加，沿着脂肪酸动员标志物减少 和β-氧化，表明CR-MAT中脂解能力降低。因此，CR-MAT仓库 由于脂肪分解的代谢能力降低，可能无法接近。在我们的两个衰老模型中， MAT增加;此外，破骨细胞定位于老年小鼠骨骼和骨骼中的MAT， 再吸收、炎症和线粒体生物发生的标记物增加。我们因此 假设在热量充足的非老年条件下，运动消耗MAT， 然而，在CR和可能的老化中，MAT的运动利用支持骨 猫在SA 1中，我们将询问MAT和骨骼在卡路里限制期间对运动的反应。 在SA 2中，我们确定了MAT和骨骼在衰老过程中对运动的反应。该提案使用 创新的技术来量化，定位和代谢表型MAT。一只记者鼠 将用于识别新分化的骨髓脂肪细胞，并在细胞内进行表征。 水平-MAT是否由于脂质摄取或由于CR中MSC谱系转换而增加。在SA 2中， 除了生理老化外，还将使用早衰小鼠模型来测试骨和MAT。 对锻炼的反应。结合体积MAT测量、脂肪细胞谱系示踪、组织学 MAT的分子分析、代谢能力测量以及骨微结构 通过微CT、生物力学测试和动态组织形态测量， 关于MAT在CR和衰老背景下的代谢功能的基本问题， 以及它与骨骼健康的关系