Metabolism and functions of bone marrow adipose tissue in the marrow niche - Abstract Whilst functions of subcutaneous and visceral white adipose tissues (WAT) have been extensively analyzed, roles of adipocytes within other depots have not been fully investigated. One population of particular importance are bone marrow adipocytes (BMAds), which functionally interact with hematopoietic cells, osteoblasts, and osteoclasts to influence the homeostasis of blood cell formation and bone remodeling. Although potential connections between bone marrow adipose tissue (BMAT) and hematopoietic and bone metabolism have been speculated on for decades, rigorous validation and mechanistic studies have been limited by the lack of BMAd-specific animal models. We created a novel BMAd-specific Cre mouse model, that uses an intersectional strategy with dual recombinases: Osterix-FLPo and FLPo-dependent Adipoq-Cre (FAC) to stimulate recombination of floxed alleles predominantly in BMAd populations. Taking advantage of this novel BMAd-Cre mouse model, we found that BMAd lipolysis (i.e. Pnpla2) is necessary for myelopoiesis and osteoblast functions under conditions of energy deficit, suggesting that BMAds supply fuel substrates to other cells within the marrow niche. We then created mice lacking BMAds, and found that, in toto, BMAds suppress endocortical bone formation but are required for maintaining hematopoietic stem/progenitor cell pools. There are several open questions in the field. How does BMAT increase with caloric restriction (CR) whereas WAT decreases? What are the molecular, metabolic, and functional differences between regulated and constitutive BMAT and WAT? How does BMAd lipid metabolism influence functioning of neighboring cells, especially hematopoiesis and osteoblasts? Our hypotheses are 1) that the selective expansion of BMAT with CR is due to increased glucose uptake and de novo lipogenesis of BMAd, 2) that molecular signatures of regulated BMAd (rBMAd), constitutive BMAd (cBMAd) and white adipocyte (WAd) reflect their unique location and regulation, and will provide insights into their local functions, and 3) that BMAd metabolism, including uptake of lipid by CD36, is critical for regulation of bone and hematopoietic cellularity through secretion of extracellular vesicles, adipokines, cytokines, and microRNAs. To test these hypotheses, we propose the following Specific Aims: 1) To identify metabolic and molecular mechanisms that cause BMAT to expand with CR, whereas WAT depots are decreased. 2) To investigate molecular and functional characteristics of rBMAds, cBMAds, and WAds. 3) To investigate roles and mechanisms of BMAd metabolism in the regulation of bone and hematopoietic cellularity.
