Obesity and Type 2 diabetes represent states of chronic inflammation, and much has been learned about how the soluble mediators and signaling intermediates of immunity disrupt normal metabolic function. We do not yet understand, however, the transcriptional mechanisms by which immune factors interact with the metabolic machinery. Our laboratory has discovered that interferon regulatory factors (IRFs) are expressed in adipose tissue and that IRF4 in particular plays a major role in adipocyte differentiation, lipolysis and lipogenesis. In the current proposal, we focus on the related molecule IRF3, which is a well-studied pro-inflammatory transcription factor. IRF3 is of particular interest because it is activated by two kinases, TBK1 and IKKe, that are known to be up-regulated in obesity. Furthermore, pharmacological or genetic disruption of IKKe promotes leanness and insulin sensitivity in high-fat fed mice. Interestingly, we have discovered that mice lacking IRF3 appear to phenocopy these effects, and show reduced adiposity with enhanced thermogenesis in white fat (i.e. `browning'). Furthermore, Irf3-/- mice are completely protected from hepatic steatosis. We have now shown that IRF3 binds to and inhibits the transcriptional co-activator PGC-1a, and we hypothesize that the phenotype of the Irf3-/- mice may reflect the acquisition of unchecked PGC-1a activity. Here we describe experiments to determine if IRF3 is activated in liver and fat of obese animals, and to study the mechanisms by which IRF3 acts to inhibit thermogenesis and fatty acid oxidation.

Public Health Relevance

Inflammation and metabolism are tightly linked processes with consequences for human diseases such as obesity and Type 2 diabetes. Despite the identification of many avenues of molecular cross-talk between them, little is known about the transcriptional pathways that underlie the effects of inflammation on metabolic function. We have identified the transcription factor IRF3 as a key mediator by which inflammation promotes fat accumulation and glucose intolerance in vitro and in vivo. Here we propose to identify the mechanisms by which IRF3 exerts its detrimental effects on metabolic health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK102170-05
Application #
9626903
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Haft, Carol R
Project Start
2015-04-01
Project End
2020-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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
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
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

Showing the most recent 10 out of 14 publications