PROJECT SUMMARY A great deal of our understanding of the process of adipogenesis has come from in vitro studies on cultured cell lines and adipose stromal fractions, focusing on the differentiation of committed preadipocytes into mature lipid-laden adipocytes. These studies have provided a wealth of knowledge, including elucidating an elegant cascade of mostly transcription factors that propels preadipocytes through the differentiation process into mature adipocytes. However, there is still a large knowledge gap in our understanding of the integrated factors that trigger this adipogenesis cascade in vivo and the influence of these pathways on the development of obesity and metabolic disease. Our proposal is focused on addressing these knowledge gaps. We identified a pathway in adipose tissue that is responsive to changes in diet and regulates endogenous adipocyte precursor cell (APC) activity. We found that ADAMTS1 is a critical mediator of this pathway that gates a depot-specific decision to induce adipogenesis in response to high-fat diet. We will test and define the function of this pathway in physiological mechanisms that regulate the initiation of the differentiation program in APCs. Using molecular and cellular approaches, as well as mouse models and samples from humans, we will elucidate the roles, mechanisms and relevance to human physiology of the Adamts1 pathway in the in vivo regulation of adipogenesis. In addition, we will reveal how this pathway modulates the systemic stimulus of high-fat diet to generate context-specific responses in the adipose tissue during diet-induced obesity. These studies will provide an integrated perspective on how this pathway functions to regulate adipogenesis and in the pathogenesis of obesity and insights into the implications for metabolism.