Zfp423 in the Control of Preadipocyte Determination

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DESCRIPTION (provided by applicant): The global epidemic of obesity is alarming, as obesity is a significant risk factor for numerous chronic disorders such as type 2 diabetes, cancer, and cardiovascular disease. Manipulating the adipose lineage may represent a novel therapeutic treatment for obesity and associated diseases; however, any attempts will depend on a deeper understanding of the basic mechanisms controlling adipocyte development. My career goal is to become a leading independent investigator in the burgeoning field of adipose development, with particular focus on the developmental mechanisms controlling the initial specification of different adipose depots in vivo. My postdoctoral research to date in Dr. Bruce Spiegelman's laboratory at the Dana-Farber Cancer Institute has focused on the discovery of transcriptional regulators of preadipocyte determination. Our recent discovery of the transcription factor Zfp423 as a preadipocyte-enriched regulator of preadipocyte commitment crucial for adipocyte development in vitro and in vivo has opened up the possibility of 1) developing tools to localize and isolate committed preadipocytes found in vivo, and 2) elucidate the molecular mechanisms controlling commitment to the adipose lineage. In Specific Aim 1 we will utilize BAC transgenic mice expressing GFP under the control of Zfp423 cis-regulatory elements to localize and isolate preadipocytes in various adult fat depots as well as in developing mouse embryos, and demonstrate their commitment to the adipose lineage. In Specific Aim 2 we will elucidate the molecular mechanisms of preadipocyte determination through biochemical analysis of Zfp423 function and interacting partners. These experiments will reveal the anatomical location of committed preadipocytes during mouse development, establish a novel tool for the purification of adipose precursors in mice, determine the molecular mechanisms by which Zfp423 controls preadipocyte determination, and importantly, identify novel regulators of the preadipose state. A deeper understanding of these unexplored areas of adipose biology will facilitate our attempts to manipulate the adipose lineage as a therapeutic treatment for obesity and metabolic disease. The support of this career development award and the experience derived from carrying out these experiments will facilitate my transition to an independent investigator in the field of adipose biology. PUBLIC HEALTH RELEVANCE: The rising incidence of obesity has increased the urgency of understanding the fundamental systems controlling energy homeostasis, including the formation of fat tissue. The experiments described in this proposal will establish and utilize an important tool for studying fat cell precursors in mice, and reveal the molecular mechanisms controlling fat cell development. This knowledge will facilitate our attempts to manipulate fat tissue biology as a therapeutic treatment for obesity and metabolic disease.