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.
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.
|Shen, Yachen; Roh, Hyun Cheol; Kumari, Manju et al. (2017) Adipocyte glucocorticoid receptor is important in lipolysis and insulin resistance due to exogenous steroids, but not insulin resistance caused by high fat feeding. Mol Metab 6:1150-1160|
|Kazak, Lawrence; Chouchani, Edward T; Stavrovskaya, Irina G et al. (2017) UCP1 deficiency causes brown fat respiratory chain depletion and sensitizes mitochondria to calcium overload-induced dysfunction. Proc Natl Acad Sci U S A 114:7981-7986|
|Campbell, John N; Macosko, Evan Z; Fenselau, Henning et al. (2017) A molecular census of arcuate hypothalamus and median eminence cell types. Nat Neurosci 20:484-496|
|Roh, Hyun Cheol; Tsai, Linus T-Y; Lyubetskaya, Anna et al. (2017) Simultaneous Transcriptional and Epigenomic Profiling from Specific Cell Types within Heterogeneous Tissues In Vivo. Cell Rep 18:1048-1061|
|Kazak, Lawrence; Chouchani, Edward T; Lu, Gina Z et al. (2017) Genetic Depletion of Adipocyte Creatine Metabolism Inhibits Diet-Induced Thermogenesis and Drives Obesity. Cell Metab 26:660-671.e3|
|You, Dongjoo; Nilsson, Emma; Tenen, Danielle E et al. (2017) Dnmt3a is an epigenetic mediator of adipose insulin resistance. Elife 6:|
|Kumari, Manju; Wang, Xun; Lantier, Louise et al. (2016) IRF3 promotes adipose inflammation and insulin resistance and represses browning. J Clin Invest 126:2839-54|
|Kang, Sona; Tsai, Linus T-Y; Rosen, Evan D (2016) Nuclear Mechanisms of Insulin Resistance. Trends Cell Biol 26:341-351|
|Rosen, E D (2016) Epigenomic and transcriptional control of insulin resistance. J Intern Med 280:443-456|
|Jeffery, Elise; Berry, Ryan; Church, Christopher D et al. (2014) Characterization of Cre recombinase models for the study of adipose tissue. Adipocyte 3:206-11|
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