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

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

doi:10.1016/j.celrep.2016.06.024

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

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 WooPaul J. Utz, Michael Glogauer, Edgar Engleman, Shawn Winer, Daniel A. Winer

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Abstract

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.

Original language	English (US)
Pages (from-to)	717-730
Number of pages	14
Journal	Cell reports
Volume	16
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2016.06.024
State	Published - Jul 19 2016
Externally published	Yes

Bibliographical note

Funding 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.

Publisher Copyright:
© 2016 The Author(s)

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Revelo, X. S., Ghazarian, M., Chng, M. H. Y., Luck, H., Kim, J. H., Zeng, K., Shi, S. Y., Tsai, S., Lei, H., Kenkel, J., Liu, C. L., Tangsombatvisit, S., Tsui, H., Sima, C., Xiao, C., Shen, L., Li, X., Jin, T., Lewis, G. F., ... Winer, D. A. (2016). Nucleic Acid-Targeting Pathways Promote Inflammation in Obesity-Related Insulin Resistance. Cell reports, 16(3), 717-730. https://doi.org/10.1016/j.celrep.2016.06.024

Revelo, XS, Ghazarian, M, Chng, MHY, Luck, H, Kim, JH, Zeng, K, Shi, SY, Tsai, S, Lei, H, Kenkel, J, Liu, CL, Tangsombatvisit, S, Tsui, H, Sima, C, Xiao, C, Shen, L, Li, X, Jin, T, Lewis, GF, Woo, M, Utz, PJ, Glogauer, M, Engleman, E, Winer, S & Winer, DA 2016, 'Nucleic Acid-Targeting Pathways Promote Inflammation in Obesity-Related Insulin Resistance', Cell reports, vol. 16, no. 3, pp. 717-730. https://doi.org/10.1016/j.celrep.2016.06.024

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abstract = "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.",

author = "Revelo, {Xavier S.} and Magar Ghazarian and Chng, {Melissa Hui Yen} and Helen Luck and Kim, {Justin H.} and Kejing Zeng and Shi, {Sally Y.} and Sue Tsai and Helena Lei and Justin Kenkel and Liu, {Chih Long} and Stephanie Tangsombatvisit and Hubert Tsui and Corneliu Sima and Changting Xiao and Lei Shen and Xiaoying Li and Tianru Jin and Lewis, {Gary F.} and Minna Woo and Utz, {Paul J.} and Michael Glogauer and Edgar Engleman and Shawn Winer and Winer, {Daniel A.}",

note = "Funding 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. Publisher Copyright: {\textcopyright} 2016 The Author(s)",

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AU - Luck, Helen

AU - Kim, Justin H.

AU - Zeng, Kejing

AU - Shi, Sally Y.

AU - Tsai, Sue

AU - Lei, Helena

AU - Kenkel, Justin

AU - Liu, Chih Long

AU - Tangsombatvisit, Stephanie

AU - Tsui, Hubert

AU - Sima, Corneliu

AU - Xiao, Changting

AU - Shen, Lei

AU - Li, Xiaoying

AU - Jin, Tianru

AU - Lewis, Gary F.

AU - Woo, Minna

AU - Utz, Paul J.

AU - Glogauer, Michael

AU - Engleman, Edgar

AU - Winer, Shawn

AU - Winer, Daniel A.

N1 - Funding 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. Publisher Copyright: © 2016 The Author(s)

PY - 2016/7/19

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N2 - 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.

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

Abstract

Bibliographical note

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