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; Tom Luedde

doi:10.1038/ncomms11869

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

Nat Commun. 2016 Jun 21:7:11869. doi: 10.1038/ncomms11869.

Authors

Jérémie Gautheron^{1

2}, Mihael Vucur^{1

2}, Anne T Schneider^{1

2}, Ilenia Severi³, Christoph Roderburg¹, Sanchari Roy^{1

2}, Matthias Bartneck¹, Peter Schrammen¹, Mauricio Berriel Diaz⁴, Josef Ehling⁵, Felix Gremse⁵, Felix Heymann¹, Christiane Koppe^{1

2}, Twan Lammers⁵, Fabian Kiessling⁵, Niels Van Best⁶, Oliver Pabst⁶, Gilles Courtois⁷, Andreas Linkermann⁸, Stefan Krautwald⁸, Ulf P Neumann⁹, Frank Tacke¹, Christian Trautwein¹, Douglas R Green¹⁰, Thomas Longerich¹¹, Norbert Frey¹², Mark Luedde¹², Matthias Bluher¹³, Stephan Herzig^{4

14}, Mathias Heikenwalder¹⁵, Tom Luedde^{1

2}

Affiliations

¹ Department of Medicine III, University Hospital RWTH Aachen, Aachen 52074, Germany.
² Division of GI and Hepatobiliary Oncology, University Hospital RWTH Aachen, Aachen 52074, Germany.
³ Department of Experimental and Clinical Medicine, University of Ancona, Ancona 60020, Italy.
⁴ Institute for Diabetes and Cancer IDC Helmholtz Center Munich, Neuherberg 85764 and Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine I, Heidelberg University, Heidelberg 69120, Germany.
⁵ Department for Experimental Molecular Imaging, University Clinic and Helmholtz Institute for Biomedical Engineering RWTH Aachen, Aachen 52074, Germany.
⁶ Institut of Medical Microbiology, University Hospital RWTH Aachen, Aachen 52074, Germany.
⁷ Inserm U1038, BIG, CEA, Grenoble 38054, France.
⁸ Division of Nephrology and Hypertension, Christian-Albrechts-University, Kiel 24105, Germany.
⁹ Department of Visceral and Transplantation Surgery, University Hospital RWTH Aachen, Aachen 52074, Germany.
¹⁰ Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
¹¹ Institute of Pathology, University Hospital RWTH Aachen, Aachen 52074, Germany.
¹² Department of Cardiology and Angiology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel 24105, Germany.
¹³ Department of Medicine, University of Leipzig, Leipzig 04103, Germany.
¹⁴ German Center for Diabetes Research (DZD), Neuherberg 85764, Germany.
¹⁵ Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adipocytes / enzymology
Adipocytes / pathology
Adipose Tissue, White / enzymology*
Adipose Tissue, White / pathology
Animals
Apoptosis / genetics
Body Mass Index
Caspase 8 / genetics
Caspase 8 / metabolism
Choline / metabolism
Choline Deficiency / enzymology
Choline Deficiency / etiology
Choline Deficiency / genetics*
Choline Deficiency / pathology
Diet, High-Fat
Gene Expression Regulation
Glucose Intolerance / enzymology
Glucose Intolerance / etiology
Glucose Intolerance / genetics*
Glucose Intolerance / pathology
Homeostasis
Humans
Inflammation
Insulin / metabolism
Insulin Resistance
Intra-Abdominal Fat / enzymology*
Intra-Abdominal Fat / pathology
Male
Mice
Necrosis / enzymology*
Necrosis / genetics
Necrosis / pathology
Obesity / enzymology
Obesity / etiology
Obesity / genetics*
Obesity / pathology
Receptor-Interacting Protein Serine-Threonine Kinases / genetics*
Receptor-Interacting Protein Serine-Threonine Kinases / metabolism

Substances

Insulin
Receptor-Interacting Protein Serine-Threonine Kinases
Ripk3 protein, mouse
Casp8 protein, mouse
Caspase 8
Choline

Grants and funding

208237/ERC_/European Research Council/International