Nucleic Acid-Targeting Pathways Promote Inflammation in Obesity-Related Insulin Resistance

Publication date: Available online 30 June 2016
Source:Cell Reports
Author(s): Xavier S. Revelo, Magar Ghazarian, Melissa Hui Yen Chng, Helen Luck, Justin H. Kim, Kejing Zeng, Sally Y. Shi, Sue Tsai, Helena Lei, Justin Kenkel, Chih Long Liu, Stephanie Tangsombatvisit, Hubert Tsui, Corneliu Sima, Changting Xiao, Lei Shen, Xiaoying Li, Tianru Jin, Gary F. Lewis, Minna Woo, Paul J. Utz, Michael Glogauer, Edgar Engleman, Shawn Winer, Daniel A. Winer
Obesity-related inflammation of metabolic tissues, including visceral adipose tissue (VAT) and liver, are key factors in the development of insulin resistance (IR), though many of the contributing mechanisms remain unclear. We show that nucleic-acid-targeting pathways downstream of extracellular trap (ET) formation, unmethylated CpG DNA, or ribonucleic acids drive inflammation in IR. High-fat diet (HFD)-fed mice show increased release of ETs in VAT, decreased systemic clearance of ETs, and increased autoantibodies against conserved nuclear antigens. In HFD-fed mice, this excess of nucleic acids and related protein antigens worsens metabolic parameters through a number of mechanisms, including activation of VAT macrophages and expansion of plasmacytoid dendritic cells (pDCs) in the liver. Consistently, HFD-fed mice lacking critical responders of nucleic acid pathways, Toll-like receptors (TLR)7 and TLR9, show reduced metabolic inflammation and improved glucose homeostasis. Treatment of HFD-fed mice with inhibitors of ET formation or a TLR7/9 antagonist improves metabolic disease. These findings reveal a pathogenic role for nucleic acid targeting as a driver of metabolic inflammation in IR.

Graphical abstract

Teaser

Revelo et al. show that diet-induced obesity promotes excess release and diminished clearance of nucleic acid and related antigens, with appearance of autoantibodies. Aberrant handling of nucleic acids activates VAT macrophages and liver pDCs via TLR7/9 to promote inflammation. Nucleic acid-sensing pathways may represent therapeutic targets for obesity-related metabolic disease.


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