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 identified an unsuspected transcription factor, IRF4, as a critical regulator of adipogenesis, lipolysis, lipogenesis, and thermogenesis in adipocytes. Interestingly, IRF4 is well-studied in immune cells, where it directs macrophage polarization and T cell differentiation. Here we will characterize the pathways that regulate IRF4 expression in brown and white adipocytes, and we will identify the target genes of this factor in fat. Furthermore, we will also study the post- transcriptional mechanisms by which IRF4 activity is regulated in adipocytes. These studies will involve a number of biased and unbiased approaches in vivo and in vitro. If successful, these studies will better define the biological actions of IRF4 in adipocytes. IRF4 sits at the intersection of metabolism and inflammation in adipose tissue and is thus perfectly positioned as a site of potential therapeutic intervention.

Public Health Relevance

Adipocytes play a role in almost all aspects of systemic metabolism, from glucose uptake and insulin action to lipid synthesis and breakdown to heat generation. In order to perform these tasks, fat cells must respond to ambient cues (such as food availability and temperature), and then turn on and off the appropriate sets of genes. We have demonstrated that IRF4 is a key factor that coordinates these activities inside fat cells; manipulation of IRF4 has the potential to alter metabolism to promote health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK085171-07
Application #
9012814
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Haft, Carol R
Project Start
2010-04-01
Project End
2019-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
7
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
Ahmad, Rasheed; Al-Roub, Areej; Kochumon, Shihab et al. (2018) The Synergy between Palmitate and TNF-? for CCL2 Production Is Dependent on the TRIF/IRF3 Pathway: Implications for Metabolic Inflammation. J Immunol 200:3599-3611
Roh, Hyun Cheol; Tsai, Linus T Y; Shao, Mengle et al. (2018) Warming Induces Significant Reprogramming of Beige, but Not Brown, Adipocyte Cellular Identity. Cell Metab 27:1121-1137.e5
De Filippis, Elena; Li, Ting; Rosen, Evan David (2018) Exposure of adipocytes to bisphenol-A in vitro interferes with insulin action without enhancing adipogenesis. PLoS One 13:e0201122
Kong, Xingxing; Yao, Ting; Zhou, Peng et al. (2018) Brown Adipose Tissue Controls Skeletal Muscle Function via the Secretion of Myostatin. Cell Metab 28:631-643.e3
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
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
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
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
You, Dongjoo; Nilsson, Emma; Tenen, Danielle E et al. (2017) Dnmt3a is an epigenetic mediator of adipose insulin resistance. Elife 6:
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

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