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.
Bibliographical noteFunding Information:
We thank Battista Calvieri (Microscopy Imaging Lab, University of Toronto) for assistance with electron microscopy and Paul Taylor (SPARC BioCentre, The Hospital for Sick Children) for assistance with protein MS analysis. We thank the Hirano laboratory for assistance with our ELISPOT assays. This work was supported in part by Canadian Institutes of Health Research (CIHR) grants 119414, 132562, and 142708 (D.A.W.); Canadian Diabetes Association (CDA) grants OG-3-15-5014 and CS-5-12-3886 (D.A.W.); NIH grant HL075462 (E.E.); and the University of Toronto Banting and Best Diabetes Centre Sun Life New Investigator Award (D.A.W.). X.S.R. is the recipient of a CDA Postdoctoral Fellowship.