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
Affiliations
Xavier S. Revelo
Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, Canada
Magar Ghazarian
Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, Canada
Melissa Hui Yen Chng
Department of Pathology, Stanford University School of Medicine, Palo Alto, CA 94305, USA
Helen Luck
Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, Canada
Justin H. Kim
Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, Canada
Kejing Zeng
Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, Canada
Sally Y. Shi
Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, Canada
Sue Tsai
Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, Canada
Helena Lei
Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, Canada
Justin Kenkel
Department of Pathology, Stanford University School of Medicine, Palo Alto, CA 94305, USA
Chih Long Liu
Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Palo Alto, CA 94305, USA
Stephanie Tangsombatvisit
Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Palo Alto, CA 94305, USA
Hubert Tsui
Department of Pathology, University Health Network, Toronto, ON M5G 2C4, Canada
Corneliu Sima
Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, MA 02142, USA
Changting Xiao
Division of Endocrinology and Metabolism, Department of Medicine, University Health Network, Toronto, ON M5G 2C4, Canada
Lei Shen
Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, China
Xiaoying Li
Department of Endocrinology, Zhongshan Hospital, Fudan University, Shanghai 200011, China
Tianru Jin
Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, Canada
Gary F. Lewis
Division of Endocrinology and Metabolism, Department of Medicine, University Health Network, Toronto, ON M5G 2C4, Canada
Minna Woo
Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, Canada
Paul J. Utz
Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Palo Alto, CA 94305, USA
Michael Glogauer
Faculty of Dentistry, University of Toronto, Matrix Dynamics Group, Toronto, ON M5G 1G6, Canada
Edgar Engleman
Department of Pathology, Stanford University School of Medicine, Palo Alto, CA 94305, USA
Shawn Winer
Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, Canada
Daniel A. Winer
Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, Canada
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.
