Adipocytes serve as the body?s primary site for lipid storage and act as signaling centers to coordinate the physiological response to an organism?s nutritional and metabolic state. Therefore, to understand susceptibility to obesity and type 2 diabetes requires a detailed understanding of the molecules underlying the function of adipocytes. The transcription factor PPAR? is a master regulator of adipogenesis and regulates the transcription of genes involved in glucose transport, lipid metabolism, and a number of adipokines. However, the mechanism by which PPAR? regulates transcription in adipocytes remains incompletely understood. This proposal will improve our understanding of the mechanism of PPAR? transcriptional regulation by studying a novel positive regulator of PPAR? signaling, Zfp407, that was recently identified by our lab. We hypothesize that Zfp407 in adipocytes regulates cell survival by controlling PPAR? signaling as a novel scaffolding cofactor. This hypothesis is based on our preliminary data demonstrating that Zfp407 deficiency in cultured adipocytes broadly reduces the expression of PPAR? target genes while in vivo Zfp407 deficiency in adipocytes greatly reduces fat mass.
In Specific Aim 1, we will test whether constitutive and temporal deletion of Zfp407 specifically in adipocytes alters adipocyte survival and function and determine the metabolic consequences.
In Specific Aim 2, we will apply genome-wide analysis of transcription factor binding in adipocytes together with biochemical and cell biological approaches to determine the molecular mechanism by which Zfp407 regulates PPAR? activity. Collectively, these studies will improve our mechanistic understanding of adipocyte function and PPAR? signaling, which are together critical for understanding the pathophysiology of metabolic disease and discovering new therapeutic targets.
Obesity and type 2 diabetes represent major global health burdens, such that there remains a tremendous need for therapeutics that can safely maintain a healthy metabolic phenotype. Agonists of PPAR? are used clinically to treat metabolic diseases, but have limited utility due to their side effects. This proposal will provide insight into the regulation of PPAR? signaling in adipocytes, which may lead to improved treatments for obesity and type 2 diabetes.
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