REGULATION OF NUTRIENT HOMEOSTASIS BY IRF4

描述（由申请人提供）：目前肥胖和2型糖尿病的有效治疗管理是有限的。一种有希望的方法是通过脂肪细胞的“重编程”来促进卡路里消耗和增强葡萄糖稳态。然而，脂肪细胞生理学的调节需要我们了解这些细胞调节基因表达的途径。我们进行了一项无偏倚的研究，利用dna酶超敏分析、计算策略和实验生物学来确定脂肪细胞中的新型转录途径。这使我们意外地发现，干扰素调节因子（IRFs）在脂肪细胞中表达，并在脂肪细胞发育和生理中发挥功能作用。irf以其在免疫细胞中的促炎作用而闻名，但此前尚未在代谢组织中发现。在这个应用中，我们关注一个特定的IRF， IRF4，它在脂肪细胞和免疫细胞中高水平表达。我们已经证明，IRF4受禁食、喂养、胰岛素和脂肪肥胖的显著调节，并且小鼠中IRF4的缺乏与胰岛素敏感性增加有关。在这里，我们提出的实验将更好地定义IRF4在脂肪细胞中的生物学作用。具体来说，我们建议在脂肪细胞中确定促进IRF4表达的上游途径。然后，我们将在体外和体内确定IRF4在这些细胞中的作用范围。最后，我们将利用基因组技术鉴定脂肪细胞中irf4调节基因的补体。IRF4位于脂肪组织中代谢和炎症的交叉点，因此完美地定位为潜在的治疗干预位点。

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.