ABSTRACT Accumulation of bone marrow adipocytes within the skeleton has been linked to bone loss and metabolic disease. However, we know very little about the regulation and function of the mature bone marrow adipocyte. This significant gap in knowledge limits our ability to prevent the negative and target the positive actions of bone marrow adipocytes, which fill ~70% of the adult human skeleton and make up 8-13% of our total body adipose tissue stores. This information is critical to develop novel strategies for the safe, effective treatment of disorders such as osteoporosis. A key factor limiting our understanding of the pathophysiology and function of the mature bone marrow adipose tissue (BMAT) adipocyte and its contributions to bone health is the lack of in vivo models. To overcome this, we have generated a novel genetic model that allows for conditional targeting of the BMAT adipocytes. In addition, over the past 5-years, we have developed and optimized several models of selective BMAT catabolism. In this proposal, we will these models to (#1) define how direct and indirect neural regulation of BMAT contributes to bone formation and skeletal homeostasis and (#2) determine if controlled regulation of BMAT catabolism can restore lost bone in settings of metabolic and skeletal disease. Our long-term goal is to contribute to the foundational understanding of the basic cell biology and integrated physiology of the mature BMAT adipocyte. Our central hypothesis is that BMAT serves as a local energy reservoir that can be selectively catabolized to preserve or enhance local osteoblast function in states of systemic metabolic distress and neural-induced skeletal suppression. Successful completion of this work will improve our understanding of how bone health is regulated by the nervous system and how this is modified by the presence of mature bone marrow adipocytes. This will provide important insights into the causes of bone loss and osteoporosis and contribute to development of new strategies for treatment of metabolic skeletal disorders.