title: Nucleic Acid-Targeting Pathways Promote Inflammation in Obesity-Related Insulin Resistance.
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.
authors.affiliation: Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, Canada. Electronic address: xrevelo@uhnresearch.ca.
authors.forename: Xavier S
authors.initials: XS
authors.lastname: Revelo
authors.affiliation: Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Magar
authors.initials: M
authors.lastname: Ghazarian
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Palo Alto, CA 94305, USA.
authors.forename: Melissa Hui Yen
authors.initials: MH
authors.lastname: Chng
authors.affiliation: Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Helen
authors.initials: H
authors.lastname: Luck
authors.affiliation: Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Justin H
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, Canada; Department of Endocrinology and Metabolism, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China.
authors.forename: Kejing
authors.initials: K
authors.lastname: Zeng
authors.affiliation: Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Sally Y
authors.initials: SY
authors.lastname: Shi
authors.affiliation: Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Sue
authors.initials: S
authors.lastname: Tsai
authors.affiliation: Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Helena
authors.initials: H
authors.lastname: Lei
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Palo Alto, CA 94305, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Kenkel
authors.affiliation: Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Palo Alto, CA 94305, USA.
authors.forename: Chih Long
authors.initials: CL
authors.lastname: Liu
authors.affiliation: Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Palo Alto, CA 94305, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Tangsombatvisit
authors.affiliation: Department of Pathology, University Health Network, Toronto, ON M5G 2C4, Canada.
authors.forename: Hubert
authors.initials: H
authors.lastname: Tsui
authors.affiliation: Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, MA 02142, USA.
authors.forename: Corneliu
authors.initials: C
authors.lastname: Sima
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University Health Network, Toronto, ON M5G 2C4, Canada.
authors.forename: Changting
authors.initials: C
authors.lastname: Xiao
authors.affiliation: Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Endocrinology, Zhongshan Hospital, Fudan University, Shanghai 200011, China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Li
authors.affiliation: Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Tianru
authors.initials: T
authors.lastname: Jin
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University Health Network, Toronto, ON M5G 2C4, Canada.
authors.forename: Gary F
authors.initials: GF
authors.lastname: Lewis
authors.affiliation: Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, Canada; Division of Endocrinology and Metabolism, Department of Medicine, University Health Network, Toronto, ON M5G 2C4, Canada.
authors.forename: Minna
authors.initials: M
authors.lastname: Woo
authors.affiliation: Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Palo Alto, CA 94305, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Utz
authors.affiliation: Faculty of Dentistry, University of Toronto, Matrix Dynamics Group, Toronto, ON M5G 1G6, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Glogauer
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Palo Alto, CA 94305, USA.
authors.forename: Edgar
authors.initials: E
authors.lastname: Engleman
authors.affiliation: Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, Canada; Department of Laboratory Medicine, St. Michael's Hospital, Toronto, ON M5B 1W8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Shawn
authors.initials: S
authors.lastname: Winer
authors.affiliation: Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, Canada; Department of Pathology, University Health Network, Toronto, ON M5G 2C4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: dan.winer@uhn.ca.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Winer
mesh_terms: D000328:Adult; D000818:Animals; D003713:Dendritic Cells / Q000378:metabolism / Q000473:pathology; D059305:Diet, High-Fat / Q000379:methods; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology*; D007333:Insulin Resistance / Q000502:physiology*; D050152:Intra-Abdominal Fat / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009696:Nucleic Acids / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism* / Q000473:pathology*; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D009696:Nucleic Acids; D051193:Toll-Like Receptors; D005947:Glucose