The necroptosis-inducing kinase RIPK3 dampens adipose tissue inflammation and glucose intolerance

Jérémie Gautheron, Mihael Vucur, Anne T. Schneider, Ilenia Severi, Christoph Roderburg, Sanchari Roy, Matthias Bartneck, Peter Schrammen, Mauricio Berriel Diaz, Josef Ehling, Felix Gremse, Felix Heymann, Christiane Koppe, Twan Lammers, Fabian Kiessling, Niels Van Best, Oliver Pabst, Gilles Courtois, Andreas Linkermann, Stefan Krautwald, Ulf P. Neumann, Frank Tacke, Christian Trautwein, Douglas R. Green, Thomas Longerich, Norbert Frey, Mark Luedde, Matthias Bluher, Stephan Herzig, Mathias Heikenwalder and Tom Luedde ()
Additional contact information
Jérémie Gautheron: University Hospital RWTH Aachen
Mihael Vucur: University Hospital RWTH Aachen
Anne T. Schneider: University Hospital RWTH Aachen
Ilenia Severi: University of Ancona
Christoph Roderburg: University Hospital RWTH Aachen
Sanchari Roy: University Hospital RWTH Aachen
Matthias Bartneck: University Hospital RWTH Aachen
Peter Schrammen: University Hospital RWTH Aachen
Mauricio Berriel Diaz: Institute for Diabetes and Cancer IDC Helmholtz Center Munich, Neuherberg 85764 and Joint Heidelberg‐IDC Translational Diabetes Program, Inner Medicine I, Heidelberg University
Josef Ehling: University Clinic and Helmholtz Institute for Biomedical Engineering RWTH Aachen
Felix Gremse: University Clinic and Helmholtz Institute for Biomedical Engineering RWTH Aachen
Felix Heymann: University Hospital RWTH Aachen
Christiane Koppe: University Hospital RWTH Aachen
Twan Lammers: University Clinic and Helmholtz Institute for Biomedical Engineering RWTH Aachen
Fabian Kiessling: University Clinic and Helmholtz Institute for Biomedical Engineering RWTH Aachen
Niels Van Best: Institut of Medical Microbiology, University Hospital RWTH Aachen
Oliver Pabst: Institut of Medical Microbiology, University Hospital RWTH Aachen
Gilles Courtois: Inserm U1038, BIG, CEA
Andreas Linkermann: Christian‐Albrechts‐University
Stefan Krautwald: Christian‐Albrechts‐University
Ulf P. Neumann: University Hospital RWTH Aachen
Frank Tacke: University Hospital RWTH Aachen
Christian Trautwein: University Hospital RWTH Aachen
Douglas R. Green: St Jude Children’s Research Hospital
Thomas Longerich: Institute of Pathology, University Hospital RWTH Aachen
Norbert Frey: University Hospital Schleswig-Holstein, Campus Kiel
Mark Luedde: University Hospital Schleswig-Holstein, Campus Kiel
Matthias Bluher: University of Leipzig
Stephan Herzig: Institute for Diabetes and Cancer IDC Helmholtz Center Munich, Neuherberg 85764 and Joint Heidelberg‐IDC Translational Diabetes Program, Inner Medicine I, Heidelberg University
Mathias Heikenwalder: German Cancer Research Center (DKFZ)
Tom Luedde: University Hospital RWTH Aachen

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: Abstract Receptor-interacting protein kinase 3 (RIPK3) mediates necroptosis, a form of programmed cell death that promotes inflammation in various pathological conditions, suggesting that it might be a privileged pharmacological target. However, its function in glucose homeostasis and obesity has been unknown. Here we show that RIPK3 is over expressed in the white adipose tissue (WAT) of obese mice fed with a choline-deficient high-fat diet. Genetic inactivation of Ripk3 promotes increased Caspase-8-dependent adipocyte apoptosis and WAT inflammation, associated with impaired insulin signalling in WAT as the basis for glucose intolerance. Similarly to mice, in visceral WAT of obese humans, RIPK3 is overexpressed and correlates with the body mass index and metabolic serum markers. Together, these findings provide evidence that RIPK3 in WAT maintains tissue homeostasis and suppresses inflammation and adipocyte apoptosis, suggesting that systemic targeting of necroptosis might be associated with the risk of promoting insulin resistance in obese patients.

Date: 2016
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DOI: 10.1038/ncomms11869

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