This proposal will systematically address a fundamental and clinically relevant question: What is the function of bone marrow adipose tissue (MAT)? Adipocytes were identified in the marrow more than a century ago, but questions about their relevance to energy homeostasis have only recently surfaced. These questions coincide with emerging data indicating that adipose depots at different sites have distinct physiologic functions and play critical roles in the pathophysiology of both metabolic and skeletal disorders. In the current project we are focused on the structure and function of bone marrow adipocytes, a unique and understudied depot that we hypothesize is associated with growth, nutritional status, and skeletal remodeling. With pilot support from R24 NIDDK 84970, we developed an integrated and multidisciplinary research team, explored new animal and human models, applied new techniques in metabolomics, developed a virtual laboratory for investigator integration, and used innovative imaging techniques for both MAT and bone micro- architecture. We also demonstrated that: 1) marrow adipocytes have unique cell surface markers that distinguish them from adipocytes in other depots;2) MAT is dynamic, with the capacity to expand or contract in response to developmental and nutritional cues such as calorie restriction; 3) adiponectin expression and basal lipolytic rates are higher in marrow adipocytes than in adipocytes from other depots;4) MAT is closely linked to bone remodeling and bone mass in humans. Most importantly, in a translational model of chronic calorie restriction, anorexia nervosa (AN), we showed that MAT was markedly increased compared to young age-matched controls and was inversely related to bone mass and the size of other fat depots. Therefore, we propose specific aims which will test the central hypothesis that MAT is an important modulator of skeletal remodeling and is fully integrated in energy homeostasis. The three aims are:1) Determine the function of MAT relative to bone remodeling;2) Assess the metabolic status of MAT and contrast this with other adipose depots;3) Define the adipocyte progenitor(AP) and its differentiation in bone marrow, and identify the genetic, molecular, biochemical and hormonal profile of MAT.

Public Health Relevance

Excess MAT is associated with greater fracture risk and low bone mass. Understanding the function of marrow adipocytes and their relationship to skeletal remodeling will help identify patients at risk for fractures in disorders like anorexia nervosa, diabetes mellitus, multiple myeloma and age-related osteoporosis. Data generated from this project also holds promise for new therapeutic approaches to preserve bone mass.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Resource-Related Research Projects (R24)
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Special Emphasis Panel (ZDK1-GRB-J (M1))
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Malozowski, Saul N
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Maine Medical Center
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Fazeli, Pouneh K; Klibanski, Anne (2014) Anorexia nervosa and bone metabolism. Bone 66:39-45
He, Qing; Yang, Xuehui; Gong, Yan et al. (2014) Deficiency of Sef is associated with increased postnatal cortical bone mass by regulating Runx2 activity. J Bone Miner Res 29:1217-31
Fazeli, Pouneh K; Klibanski, Anne (2014) Bone metabolism in anorexia nervosa. Curr Osteoporos Rep 12:82-9
Bredella, Miriam A; Gerweck, Anu V; Barber, Lauren A et al. (2014) Effects of growth hormone administration for 6 months on bone turnover and bone marrow fat in obese premenopausal women. Bone 62:29-35
Yagi, Masashi; Arentsen, Luke; Shanley, Ryan M et al. (2014) A dual-radioisotope hybrid whole-body micro-positron emission tomography/computed tomography system reveals functional heterogeneity and early local and systemic changes following targeted radiation to the murine caudal skeleton. Calcif Tissue Int 94:544-52
Guntur, Anyonya R; Le, Phuong T; Farber, Charles R et al. (2014) Bioenergetics during calvarial osteoblast differentiation reflect strain differences in bone mass. Endocrinology 155:1589-95
Fazeli, Pouneh K; Klibanski, Anne (2014) Determinants of GH resistance in malnutrition. J Endocrinol 220:R57-65
Scheller, Erica L; Troiano, Nancy; Vanhoutan, Joshua N et al. (2014) Use of osmium tetroxide staining with microcomputerized tomography to visualize and quantify bone marrow adipose tissue in vivo. Methods Enzymol 537:123-39
Simon, Becky R; Learman, Brian S; Parlee, Sebastian D et al. (2014) Sweet taste receptor deficient mice have decreased adiposity and increased bone mass. PLoS One 9:e86454
Styner, Maya; Thompson, William R; Galior, Kornelia et al. (2014) Bone marrow fat accumulation accelerated by high fat diet is suppressed by exercise. Bone 64:39-46

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