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 #
5R01DK085171-09
Application #
9443628
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Haft, Carol R
Project Start
2010-04-01
Project End
2019-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
9
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
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