A major goal of this laboratory is to understand the molecular mechanisms by which TFs and epigenomic modification control gene expression programs that regulate adipose tissue development and function. Adipogenesis begins with an established cascade of transcription factor (TF) activity that includes collaboration between the CCAAT/enhancer binding protein ? (CEBP?) and the glucocorticoid receptor (GR). A key goal of the present proposal is to determine how CEBP? and its related paralogs bridge the transcriptional programs in multipotent stem cells and early differentiating pre-adipocytes, with a long-term objective of understanding a comprehensive TF network promoting adipose tissue development, growth and function.
Specific Aim 1 comprehensively identifies the components of active enhancers during human adipogenesis. We will perform a state-of-the-art genomic/proteomic approach to determine the chromatin-associated proteins promoting adipocyte differentiation.
Specific Aim 2 elucidates the mechanistic actions of networked TFs and co-regulators that control human adipogenesis and adipocyte function. Novel adipogenic roles for protein candidates identified in Aims 1 will be examined by mutational analysis and genome-wide approaches. As a whole, we will generate and integrate unique, orthogonal cistromic and enhancer proteomic datasets to reveal fundamental molecular mechanisms for transcriptional regulators in native chromatin. This will elucidate how CEBP proteins and GR perform unique biological functions, and address the more general question of how TFs recognize, access and act at their genomic-binding sites to control tissue-specific gene expression.
Specific Aim 3 comprehensively identifies the components of active enhancers in adipose tissue. We hypothesize that comparison of the enhancer proteomes from visceral and subcutaneous white adipose tissues and from brown adipose tissue will reveal fundamental mechanisms controlling depot-specific gene expression and uncover the set of transcriptional regulators controlling lipid metabolism in vivo. Our focus on the development and function of adipose tissue is warranted given its importance in health and disease. Indeed, adipose tissue normally benefits health, yet in excess as in obesity, it becomes a strong risk for metabolic diseases including diabetes, hyperlipidemia, hypertension and heart disease. New insights into adipose biology will enhance its translational potential to combat the harmful and growing epidemics of obesity and diabetes.

Public Health Relevance

Efforts to combat obesity with diet and exercise have not reversed the steady climb of body weight in western cultures over the last decades. This proposal aims to fight obesity by understanding and ultimately controlling fat tissue development and growth. The findings will highlight therapeutic targets against obesity, which affects up to 30% of the United States population and contributes to diabetes and other debilitating metabolic disorders including hypertension and heart disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Molecular and Cellular Endocrinology Study Section (MCE)
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Haft, Carol R
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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