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Cell Rep. 2016 Jul 19;16(3):717-30. doi: 10.1016/j.celrep.2016.06.024. Epub 2016 Jun 30.

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

Author information

1
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.
2
Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, Canada.
3
Department of Pathology, Stanford University School of Medicine, Palo Alto, CA 94305, USA.
4
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.
5
Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Palo Alto, CA 94305, USA.
6
Department of Pathology, University Health Network, Toronto, ON M5G 2C4, Canada.
7
Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, MA 02142, USA.
8
Division of Endocrinology and Metabolism, Department of Medicine, University Health Network, Toronto, ON M5G 2C4, Canada.
9
Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, China.
10
Department of Endocrinology, Zhongshan Hospital, Fudan University, Shanghai 200011, China.
11
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.
12
Faculty of Dentistry, University of Toronto, Matrix Dynamics Group, Toronto, ON M5G 1G6, Canada.
13
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.
14
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.

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.

PMID:
27373163
PMCID:
PMC6354586
DOI:
10.1016/j.celrep.2016.06.024
[Indexed for MEDLINE]
Free PMC Article

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