ABSTRACT: Patients with metabolic diseases, such as obesity, diabetes, and lipodystrophy exhibit altered bone and fat mass, fat distribution, and energy homeostasis. The underlying mechanisms involved in these dysregulations are poorly understood. Bone and fat tissue are both endocrine organs and secrete factors that regulate energy metabolism. Bone synthesizing osteoblasts and fat forming adipocytes are derived from common mesenchymal progenitors. Increased bone marrow fat and decreased bone mass is noted in osteoporosis, diabetes, and aging. Osteoporotic bones at highest risk for a fracture always exhibit increased marrow fat. These clinical observations suggest that targeting bone marrow fat may be a treatment for these diseases and for 2-million fractures in US adults that occur yearly due to osteoporosis and low bone mass. However, the origin and function of the bone marrow fat, as well as its relationship to the bone and other peripheral fat depots are not very clear. The bone marrow fat is a unique fat depot that is located adjacent to the bone and is different from either white or brown adipose tissue. In this study, we aim to identify molecular mechanisms underlying the metabolic diseases with comorbidity of the bone and fat, especially novel factors secreted by the osteoblast and osteocytes that can regulate marrow adipogenesis, peripheral fat distribution, energy homeostasis and maintenance of adult bone mass. The Runx2 transcription factor is essential for the commitment of mesenchymal progenitors to the cells of skeletal lineage. Global null mice of the Runx2 gene are embryonic lethal due to complete loss of osteoblast differentiation and bone formation. We have recently published that Runx2 is also essential for chondrocyte proliferation, hypertrophic maturation, and endochondral ossification. Our preliminary data show that selective deficiency of Runx2 in mature osteoblasts and osteocytes inhibits postnatal bone synthesis and trigger a rapid onset of osteoporosis, premature aging, and death. Runx2 activity inhibits commitment of mesenchymal cells to the adipocyte lineage. Deletion of Runx2 in osteoblasts/osteocytes results in the near absence of visceral adiposity but a dramatic increase in marrow adipogenesis. We further demonstrate that Runx2 blocks adipogenesis by altering energy metabolism and by inhibiting critical signaling from Akt and Erk in the insulin pathways. Based on the preliminary data we hypothesize that Runx2 regulated signals from mature osteoblast and osteocytes control marrow adipogenesis, peripheral fat distribution, and energy homeostasis. We will utilize novel mouse models to test our hypotheses in three specific aims. Aim 1 will examine the role of Runx2 deficient osteoblasts and osteocytes in the reciprocal maintenance of adult fat and bone mass. Aim 2 will test the requirement of osteoblast/osteocyte for marrow and peripheral adiposity, and Aim 3 will uncover molecular signals and mechanisms for energy hom...