REGULATION OF NUTRIENT HOMEOSTASIS BY IRF4

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DESCRIPTION (provided by applicant): Effective therapeutic management of obesity and Type 2 diabetes is currently limited. One promising approach involves the 'reprogramming' of adipocytes in ways that promote calorie expenditure and enhanced glucose homeostasis. Modulation of adipocyte physiology, however, requires that we understand the pathways by which these cells regulate gene expression. We have performed an unbiased study to identify novel transcriptional pathways in adipocytes, using integrated DNase hypersensitivity analysis, computational strategies, and experimental biology. This led us to the unexpected discovery that interferon regulatory factors (IRFs) are expressed in adipocytes, and play a functional role in adipocyte development and physiology. Better known for their pro-inflammatory effects in immune cells, IRFs had not been previously identified in metabolic tissues. In this application, we focus on one particular IRF, IRF4, which is expressed at high levels in adipocytes and immune cells. We have shown that IRF4 is dramatically regulated by fasting, feeding, insulin, and obesity in fat, and that lack of IRF4 in mice is associated with increased insulin sensitivity. Here we propose experiments that will better define the biological actions of IRF4 in adipocytes. Specifically, we propose to identify the upstream pathways that promote expression of IRF4 action in fat cells. We will then define the range of IRF4 actions in these cells in vitro and in vivo. Finally, we will use genomic technology to identify the complement of IRF4-regulated genes in adipocytes. IRF4 sits at the intersection of metabolism and inflammation in adipose tissue and is thus perfectly positioned as sites of potential therapeutic intervention. PUBLIC HEALTH RELEVANCE: Interferon regulatory factors sit at the intersection of inflammation and metabolism in adipocytes. Manipulating these factors will allow us to promote beneficial gene expression patterns in fat cells, with potential to alter the course of metabolic diseases like obesity and Type 2 diabetes.