The dramatic rise in the incidence of obesity in the U.S. has focused attention on the biology of the adipocyte. The experiments in this proposal are designed to address crucial questions in the area of adipogenesis, or fat cell differentiation. Specifically, these studies will focus on the control of terminal gene expression in adipocytes. Two approaches are discussed. First, we will perform both biased and unbiased screens of fat cell transcription factors in cells that lack the critical adipogenic factor PPARgamma. In this way we will isolate and characterize factors that can act downstream of PPARgamma to cause lipid accumulation or adipose gene expression. Second, we will also scan large pieces of sequence flanking genes expressed in adipocytes for regulatory motifs. In collaboration with the Whitehead Genome Center we are developing algorithms to search the human genome and to perform large scale mouse-human homology searches to identify important transcription factor binding sites. Such regulatory motifs will be used to clone and to characterize the cognate transcription factors, and will allow the discovery of novel pathways in adipogenesis.
