Nucleic Acid-Targeting Pathways Promote Inflammation in Obesity-Related Insulin Resistance
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 tra...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2016-07-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124716307641 |
| _version_ | 1819050239370199040 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Xavier S. Revelo |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T11:44:53Z |
| format | Article |
| id | doaj.art-ce5351ca2ec04a7eba5603df62077ae4 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-21T11:44:53Z |
| publishDate | 2016-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-ce5351ca2ec04a7eba5603df62077ae42022-12-21T19:05:13ZengElsevierCell Reports2211-12472016-07-0116371773010.1016/j.celrep.2016.06.024Nucleic Acid-Targeting Pathways Promote Inflammation in Obesity-Related Insulin ResistanceXavier S. Revelo0Magar Ghazarian1Melissa Hui Yen Chng2Helen Luck3Justin H. Kim4Kejing Zeng5Sally Y. Shi6Sue Tsai7Helena Lei8Justin Kenkel9Chih Long Liu10Stephanie Tangsombatvisit11Hubert Tsui12Corneliu Sima13Changting Xiao14Lei Shen15Xiaoying Li16Tianru Jin17Gary F. Lewis18Minna Woo19Paul J. Utz20Michael Glogauer21Edgar Engleman22Shawn Winer23Daniel A. Winer24Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, CanadaDivision of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, CanadaDepartment of Pathology, Stanford University School of Medicine, Palo Alto, CA 94305, USADivision of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, CanadaDivision of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, CanadaDivision of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, CanadaDivision of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, CanadaDivision of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, CanadaDivision of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, CanadaDepartment of Pathology, Stanford University School of Medicine, Palo Alto, CA 94305, USADepartment of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Palo Alto, CA 94305, USADepartment of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Palo Alto, CA 94305, USADepartment of Pathology, University Health Network, Toronto, ON M5G 2C4, CanadaDepartment of Applied Oral Sciences, The Forsyth Institute, Cambridge, MA 02142, USADivision of Endocrinology and Metabolism, Department of Medicine, University Health Network, Toronto, ON M5G 2C4, CanadaShanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, ChinaDepartment of Endocrinology, Zhongshan Hospital, Fudan University, Shanghai 200011, ChinaDivision of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, CanadaDivision of Endocrinology and Metabolism, Department of Medicine, University Health Network, Toronto, ON M5G 2C4, CanadaDivision of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, CanadaDepartment of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Palo Alto, CA 94305, USAFaculty of Dentistry, University of Toronto, Matrix Dynamics Group, Toronto, ON M5G 1G6, CanadaDepartment of Pathology, Stanford University School of Medicine, Palo Alto, CA 94305, USADivision of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, CanadaDivision of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, CanadaObesity-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.http://www.sciencedirect.com/science/article/pii/S2211124716307641 |
| spellingShingle | 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 Nucleic Acid-Targeting Pathways Promote Inflammation in Obesity-Related Insulin Resistance Cell Reports |
| title | Nucleic Acid-Targeting Pathways Promote Inflammation in Obesity-Related Insulin Resistance |
| title_full | Nucleic Acid-Targeting Pathways Promote Inflammation in Obesity-Related Insulin Resistance |
| title_fullStr | Nucleic Acid-Targeting Pathways Promote Inflammation in Obesity-Related Insulin Resistance |
| title_full_unstemmed | Nucleic Acid-Targeting Pathways Promote Inflammation in Obesity-Related Insulin Resistance |
| title_short | Nucleic Acid-Targeting Pathways Promote Inflammation in Obesity-Related Insulin Resistance |
| title_sort | nucleic acid targeting pathways promote inflammation in obesity related insulin resistance |
| url | http://www.sciencedirect.com/science/article/pii/S2211124716307641 |
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