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)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1-GRB-J (M1))
Program Officer
Malozowski, Saul N
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Maine Medical Center
United States
Zip Code
Rodeheffer, Matthew S; Horowitz, Mark C (2016) Fat Decisions: Leptin Regulates Bone versus Fat in the Marrow. Cell Stem Cell 18:684-6
Shanbhogue, Vikram V; Mitchell, Deborah M; Rosen, Clifford J et al. (2016) Type 2 diabetes and the skeleton: new insights into sweet bones. Lancet Diabetes Endocrinol 4:159-73
Reagan, Michaela R; Rosen, Clifford J (2016) Navigating the bone marrow niche: translational insights and cancer-driven dysfunction. Nat Rev Rheumatol 12:154-68
Ge, Chunxi; Cawthorn, William P; Li, Yan et al. (2016) Reciprocal Control of Osteogenic and Adipogenic Differentiation by ERK/MAP Kinase Phosphorylation of Runx2 and PPARγ Transcription Factors. J Cell Physiol 231:587-96
Cawthorn, William P; Scheller, Erica L; Parlee, Sebastian D et al. (2016) Expansion of Bone Marrow Adipose Tissue During Caloric Restriction Is Associated With Increased Circulating Glucocorticoids and Not With Hypoleptinemia. Endocrinology 157:508-21
Abbott, Rosalyn D; Wang, Rebecca Y; Reagan, Michaela R et al. (2016) The Use of Silk as a Scaffold for Mature, Sustainable Unilocular Adipose 3D Tissue Engineered Systems. Adv Healthc Mater 5:1667-77
Suchacki, Karla J; Cawthorn, William P; Rosen, Clifford J (2016) Bone marrow adipose tissue: formation, function and regulation. Curr Opin Pharmacol 28:50-6
Devlin, M J; Brooks, D J; Conlon, C et al. (2016) Daily leptin blunts marrow fat but does not impact bone mass in calorie-restricted mice. J Endocrinol 229:295-306
Fairfield, Heather; Falank, Carolyne; Avery, Lindsey et al. (2016) Multiple myeloma in the marrow: pathogenesis and treatments. Ann N Y Acad Sci 1364:32-51
Plummer, Jason; Park, Miri; Perodin, Frantz et al. (2016) Methionine-restricted diet increases miRNAs that can target RUNX2 expression and alters bone structure in young mice. J Cell Biochem :

Showing the most recent 10 out of 84 publications