The goals of our research program are to determine the molecular mechanisms by which extracellular signals regulate mesenchymal cell fate decisions, and to improve our understanding of adipocyte metabolism. Mesenchymal stem cells have the capacity to differentiate into a number of cell types, including adipocytes,osteoblasts and myocytes. The focus of my lab has been on defining the genetic program of adipogenesis and its regulation by Wnt signaling. However, we are now extending this line of research to factors that determine whether stem cells differentiate into adipocytes or osteoblasts, and signals that mediate the interplay between the mature differentiated cell types. Understanding the differentiation and functional interactions these two cell types is relevant to human physiology because in a variety of clinical conditions, decreases in bone mass are typically accompanied by increases in marrow adipocytes. We have pioneered investigations into the role of Wnt10b as an inhibitor of adipogenesis in cultured preadipocytes and in transgenic mice. In addition to having less adipose tissue, mice that express Wnt10b in adipocytes and bone marrow have a four-fold increase in trabecular bone. This appears to be a direct effect of Wnt10b on fate of mesenchymal precursors because activation of Wnt signaling in pluripotent cell lines increases osteoblastogenesis and decreases adipogenesis. Evidence that it is Wnt10b that specifically plays a role in fate of mesenchymal stem cells comes from our observation that Wnt10b -/- mice have ~30% less trabecular bone. As Wnt10b expression declines in mice as they age, this signaling molecule may be integral to the increase in adiposity and decrease in bone and muscle that occurs after midlife. Our recent studies indicate that Wnt signaling in adipocytes increases their oxidative capacity through increased mitochondrial biogenesis, and that suppression of Wnt signaling by Sfrp5 is required for adipose tissue expansion. Understanding the role of Wnt signaling in the development of adipose tissues, bone, and muscle will provide important insight into the medical problems of obesity, type II diabetes, and osteoporosis, all major health risks in the United States.