Our long-term goal is to determine the origin and function of marrow adipose tissue (MAT), its relationship to nutrient status and its effects on skeletal remodeling. The R24 Collaboratory has developed a `team science' approach to address this goal by having the resources and talents of each investigative team (MacDougald [Michigan], Horowitz [Yale], Klibanski [Harvard], and Rosen [MMCRI]) working synergistically on each aim. The initial inquiry about the function of marrow fat originated from the observation that in the opposing clinical syndromes of anorexia nervosa and obesity, significant MAT was reported. Subsequently, we used resources from the R24 Collaboratory to establish that MAT is a unique, biologically active, adipose depot that reflects metabolic status and influences skeletal remodeling. We developed mouse models, lineage-tracing methodology, novel imaging technology and metabolomics to better understand MAT. As part of this translational platform, we also incorporated parallel human and animal models to address our overall goals. We demonstrated that in humans and mice, states of induced marrow adiposity by a high fat diet (HFD) or chronic caloric restriction, are associated with low BMD (2-6). We also noted for the first time that increases in MAT are due to induction of a unique type of adipocyte, responsive to environmental or nutrient stress, with endocrine and paracrine properties (7). Our overarching hypothesis for this renewal is that MAT expands through differentiation of a developmentally distinct marrow adipocyte progenitor (MAP), resulting in a dynamic secretory depot with a unique capacity to regulate the flux of circulating fatty acids and lipids during acute and chronic nutritional stresses. We also hypothesize that this depot contributes to the regulation of whole body metabolism and bone remodeling through paracrine and endocrine means. To test those hypotheses, we propose 2 aims: 1.To determine how nutrient changes affect skeletal remodeling and MAT in rodents and humans. This will be accomplished through 3 subaims: 1st, we will study the skeletal effects of a HFD in four mouse models with different marrow adiponectin levels; 2nd, we will examine how high fat feeding and fasting affects skeletal remodeling and MAT in humans; 3rd, we will investigate mechanisms for regulating lipid saturation within MAT depots, and whether secretion of palmitate and other saturated lipids from regulated MAT is detrimental to bone; in addition, we will develop animal models to specifically and inducibly modulate genes within MAT. 2. To define the adipocyte progenitor in mouse and human MAT. This will be achieved by studies in mice and man using double reporter models to delete specific genes within the marrow, and human bone marrow aspirates to definitively identify the marrow adipocyte progenitor (MAP). In summary, in this proposal we will use an integrated approach and team science for these two aims to define the functional significance and origin of MAT.
The R24 Collaboratory is committed to identifying the origin and function of marrow adipose tissue (MAT) and its relationship to the skeleton. Our discoveries to date and in the future will enhance the scientific community's capability to measure this in depth and to define its role in health and disease. Furthermore, if we find that high MAT is a risk factor for future fractures, our work should have immediate translational implications for the prevention of osteoporosis.
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