Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance
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- Antonios Chatzigeorgiou
- Department of Clinical Pathobiochemistry, Technische Universität Dresden, 01307 Dresden, Germany;
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- Tom Seijkens
- Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands;
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- Barbara Zarzycka
- Department of Biochemistry, University of Maastricht, 6229 ER, Maastricht, The Netherlands;
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- David Engel
- Department of Pathology, University of Maastricht, 6229 ER, Maastricht, The Netherlands;
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- Marjorie Poggi
- Department of Pathology, University of Maastricht, 6229 ER, Maastricht, The Netherlands;
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- Susan van den Berg
- Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands;
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- Sjoerd van den Berg
- Department of Human Genetics, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands;
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- Oliver Soehnlein
- Department of Pathology, Academic Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands;
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- Holger Winkels
- Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands;
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- Linda Beckers
- Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands;
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- Dirk Lievens
- Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands;
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- Ann Driessen
- Department of Pathology, University of Antwerp, 2650 Antwerp, Belgium;
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- Pascal Kusters
- Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands;
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- Erik Biessen
- Department of Pathology, University of Maastricht, 6229 ER, Maastricht, The Netherlands;
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- Ruben Garcia-Martin
- Department of Clinical Pathobiochemistry, Technische Universität Dresden, 01307 Dresden, Germany;
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- Anne Klotzsche-von Ameln
- Department of Clinical Pathobiochemistry, Technische Universität Dresden, 01307 Dresden, Germany;
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- Marion Gijbels
- Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands;
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- Randolph Noelle
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03766;
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- Louis Boon
- Bioceros BV, 3584 CM, Utrecht, The Netherlands;
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- Tilman Hackeng
- Department of Biochemistry, University of Maastricht, 6229 ER, Maastricht, The Netherlands;
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- Klaus-Martin Schulte
- Department of Endocrine Surgery, King's College Hospital, Denmark Hill, London SE5 9RS, United Kingdom;
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- Aimin Xu
- Department of Medicine, University of Hong Kong, Hong Kong, China;
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- Gert Vriend
- Centre for Molecular and Biomolecular Informatics, Radboud University Medical Center, 6295 EN, Nijmegen, The Netherlands;
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- Sander Nabuurs
- Centre for Molecular and Biomolecular Informatics, Radboud University Medical Center, 6295 EN, Nijmegen, The Netherlands;
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- Kyoung-Jin Chung
- Department of Clinical Pathobiochemistry, Technische Universität Dresden, 01307 Dresden, Germany;
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- Ko Willems van Dijk
- Department of Human Genetics, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands;
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- Patrick C. N. Rensen
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands;
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- Norbert Gerdes
- Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands;
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- Menno de Winther
- Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands;
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- Norman L. Block
- Divisions of Endocrinology and Hematology–Oncology, Departments of Pathology and Medicine, University of Miami Miller School of Medicine, Miami, FL 33136;
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- Andrew V. Schally
- Divisions of Endocrinology and Hematology–Oncology, Departments of Pathology and Medicine, University of Miami Miller School of Medicine, Miami, FL 33136;
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- Christian Weber
- Department of Biochemistry, University of Maastricht, 6229 ER, Maastricht, The Netherlands;
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- Stefan R. Bornstein
- Department of Medicine, Technische Universität Dresden, 01307 Dresden, Germany;
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- Gerry Nicolaes
- Department of Biochemistry, University of Maastricht, 6229 ER, Maastricht, The Netherlands;
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- Triantafyllos Chavakis
- Department of Clinical Pathobiochemistry, Technische Universität Dresden, 01307 Dresden, Germany;
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- Esther Lutgens
- Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands;
書誌事項
- 公開日
- 2014-02-03
- DOI
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- 10.1073/pnas.1400419111
- 公開者
- Proceedings of the National Academy of Sciences
この論文をさがす
説明
<jats:title>Significance</jats:title> <jats:p>Inflammation is a critical contributor to the pathogenesis of metabolic disorders associated with obesity. A group of molecules crucial in regulating the immune system are costimulatory molecules, including CD40. Our current study shows that CD40 acts as a double-edged sword in the metabolic syndrome through the initiation of differential signaling cascades. The CD40-TNF receptor-associated factor (TRAF) 2/3/5 signaling pathway protects against metabolic dysfunction and inflammation associated with obesity; conversely, the CD40-TRAF6 pathway contributes to the detrimental consequences of obesity. In the present study, we therefore designed, validated, and used a small-molecule inhibitor that blocks CD40-TRAF6 interactions. The improvement of insulin resistance by this specific CD40-TRAF6 inhibitor could represent a therapeutic breakthrough in the field of immunometabolism.</jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 111 (7), 2686-2691, 2014-02-03
Proceedings of the National Academy of Sciences
