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 ?-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 CT, 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.
Age and body mass index are among the most significant clinical determinants of fracture risk. We propose a distinct bone-fat phenotype in osteoporotic conditions (calorie restriction and aging) and ask how this phenotype supports or harms bone quality. Exercise, a known regulator of bone and bone-fat, will be applied to investigate bone-fat in these states. These proposed pre-translational aims should lead to strategies to study/direct the bone- fat depot to improve skeletal and metabolic health.
