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. A better understand of the molecules underlying adipocyte regulation and function will improve our knowledge of the pathophysiology of obesity and type 2 diabetes, which are associated with altered adipocyte function. This proposal will define the metabolic and molecular effects of a poorly understood transcription factor, Zfp407, that was recently identified by our lab as a critical molecule for adipocyte function and insulin sensitivity. We showed that Zfp407 deficiency has broad effects on adipocyte gene expression and results in reduced fat mass, illustrating the critical role of Zfp407 in adipose biology. However, the detailed physiological significance of Zfp407 and cellular mechanisms underlying them remain poorly understood. We propose three Aims to identify the critical physiological role of Zfp407 in differentiating and mature adipocytes and to determine the molecular mechanism by which Zfp407 controls gene expression in adipocytes.
In Specific Aim 1, we will discover the physiological function of Zfp407 in mature adipocytes by testing whether constitutive and temporal deletion of Zfp407 in adipocytes alters adipocyte number, survival, and function and determining the metabolic consequences under normal and obesogenic conditions.
In Specific Aim 2, we will elucidate the role and mechanism of Zfp407 in the differentiation of white, brown, and beige adipocytes.
In Specific Aim 3, we will determine the molecular mechanism by which Zfp407 regulates the adipocyte transcriptome via PPAR?-dependent and PPAR?-independent mechanisms by combining state-of-the-art genomic approaches such as GRO-Seq and BRIC-Seq with classic biochemical techniques. Collectively, these studies will improve our mechanistic understanding of how the regulation of gene expression controls adipocyte differentiation and function. These data will improve our understanding of the pathophysiology of metabolic disease and may identify new translational opportunities for treating obesity and type 2 diabetes.
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. A better understanding of adipocyte gene regulation can provide novel insights that help identify new clinical approaches for treating metabolic disease. This proposal will uncover new mechanisms of adipocyte gene regulation by investigating a poorly understood factor, Zfp407, that is essential for adipose tissue development and controls the activity of the master regulator of adipocyte function, PPAR?, as well as other novel PPAR?-independent mechanisms of gene regulation in adipocytes.
