TY - JOUR
T1 - IRF3 promotes adipose inflammation and insulin resistance and represses browning
AU - Kumari, Manju
AU - Wang, Xun
AU - Lantier, Louise
AU - Lyubetskaya, Anna
AU - Eguchi, Jun
AU - Kang, Sona
AU - Tenen, Danielle
AU - Roh, Hyun Cheol
AU - Kong, Xingxing
AU - Kazak, Lawrence
AU - Ahmad, Rasheed
AU - Rosen, Evan D.
N1 - Funding Information:
This work was funded by NIH R01 DK085171 and DK102170 to E.D. Rosen, and by funds from the Dasman Diabetes Institute and the Kuwait Foundation for the Advancement of Sciences. We thank Ines Sousa Lima for assistance in insulin signaling studies. Eleanna DeFilippis, Linus Tsai, and Su Xu provided technical support and helpful discussions. Valerie Atizado and Puthiyaveetil Shihab helped with IHC and qRT-PCR of human samples, respectively. We also thank the Vanderbilt Mouse Metabolic Phenotyping Center (DK059637) for performing the hyperinsulinemic-euglycemic clamps. The Vanderbilt University Hormone Assay and Analytical Core performed the hormone analysis (DK059637 and DK020593)
PY - 2016/8/1
Y1 - 2016/8/1
N2 - The chronic inflammatory state that accompanies obesity is a major contributor to insulin resistance and other dysfunctional adaptations in adipose tissue. Cellular and secreted factors promote the inflammatory milieu of obesity, but the transcriptional pathways that drive these processes are not well described. Although the canonical inflammatory transcription factor NF-κB is considered to be the major driver of adipocyte inflammation, members of the interferon regulatory factor (IRF) family may also play a role in this process. Here, we determined that IRF3 expression is upregulated in the adipocytes of obese mice and humans. Signaling through TLR3 and TLR4, which lie upstream of IRF3, induced insulin resistance in murine adipocytes, while IRF3 knockdown prevented insulin resistance. Furthermore, improved insulin sensitivity in IRF3-deficient mice was associated with reductions in intra-adipose and systemic inflammation in the high fat-fed state, enhanced browning of subcutaneous fat, and increased adipose expression of GLUT4. Taken together, the data indicate that IRF3 is a major transcriptional regulator of adipose inflammation and is involved in maintaining systemic glucose and energy homeostasis.
AB - The chronic inflammatory state that accompanies obesity is a major contributor to insulin resistance and other dysfunctional adaptations in adipose tissue. Cellular and secreted factors promote the inflammatory milieu of obesity, but the transcriptional pathways that drive these processes are not well described. Although the canonical inflammatory transcription factor NF-κB is considered to be the major driver of adipocyte inflammation, members of the interferon regulatory factor (IRF) family may also play a role in this process. Here, we determined that IRF3 expression is upregulated in the adipocytes of obese mice and humans. Signaling through TLR3 and TLR4, which lie upstream of IRF3, induced insulin resistance in murine adipocytes, while IRF3 knockdown prevented insulin resistance. Furthermore, improved insulin sensitivity in IRF3-deficient mice was associated with reductions in intra-adipose and systemic inflammation in the high fat-fed state, enhanced browning of subcutaneous fat, and increased adipose expression of GLUT4. Taken together, the data indicate that IRF3 is a major transcriptional regulator of adipose inflammation and is involved in maintaining systemic glucose and energy homeostasis.
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U2 - 10.1172/JCI86080
DO - 10.1172/JCI86080
M3 - Article
C2 - 27400129
AN - SCOPUS:84987786665
SN - 0021-9738
VL - 126
SP - 2839
EP - 2854
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 8
ER -
