The necroptosis-inducing kinase RIPK3 dampens adipose tissue inflammation and glucose intolerance.
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.
Department of Medicine III, University Hospital RWTH Aachen, Aachen 52074, Germany.|Division of GI and Hepatobiliary Oncology, University Hospital RWTH Aachen, Aachen 52074, Germany.
Jérémie
J
Gautheron
Department of Medicine III, University Hospital RWTH Aachen, Aachen 52074, Germany.|Division of GI and Hepatobiliary Oncology, University Hospital RWTH Aachen, Aachen 52074, Germany.
Mihael
M
Vucur
Department of Medicine III, University Hospital RWTH Aachen, Aachen 52074, Germany.|Division of GI and Hepatobiliary Oncology, University Hospital RWTH Aachen, Aachen 52074, Germany.
Anne T
AT
Schneider
Department of Experimental and Clinical Medicine, University of Ancona, Ancona 60020, Italy.
Ilenia
0000-0002-3985-1131
I
Severi
Department of Medicine III, University Hospital RWTH Aachen, Aachen 52074, Germany.
Christoph
C
Roderburg
Department of Medicine III, University Hospital RWTH Aachen, Aachen 52074, Germany.|Division of GI and Hepatobiliary Oncology, University Hospital RWTH Aachen, Aachen 52074, Germany.
Sanchari
S
Roy
Department of Medicine III, University Hospital RWTH Aachen, Aachen 52074, Germany.
Matthias
M
Bartneck
Department of Medicine III, University Hospital RWTH Aachen, Aachen 52074, Germany.
Peter
P
Schrammen
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.
Mauricio Berriel
MB
Diaz
Department for Experimental Molecular Imaging, University Clinic and Helmholtz Institute for Biomedical Engineering RWTH Aachen, Aachen 52074, Germany.
Josef
J
Ehling
Department for Experimental Molecular Imaging, University Clinic and Helmholtz Institute for Biomedical Engineering RWTH Aachen, Aachen 52074, Germany.
Felix
F
Gremse
Department of Medicine III, University Hospital RWTH Aachen, Aachen 52074, Germany.
Felix
F
Heymann
Department of Medicine III, University Hospital RWTH Aachen, Aachen 52074, Germany.|Division of GI and Hepatobiliary Oncology, University Hospital RWTH Aachen, Aachen 52074, Germany.
Christiane
C
Koppe
Department for Experimental Molecular Imaging, University Clinic and Helmholtz Institute for Biomedical Engineering RWTH Aachen, Aachen 52074, Germany.
Twan
T
Lammers
Department for Experimental Molecular Imaging, University Clinic and Helmholtz Institute for Biomedical Engineering RWTH Aachen, Aachen 52074, Germany.
Fabian
F
Kiessling
Institut of Medical Microbiology, University Hospital RWTH Aachen, Aachen 52074, Germany.
Niels
N
Van Best
Institut of Medical Microbiology, University Hospital RWTH Aachen, Aachen 52074, Germany.
Oliver
O
Pabst
Inserm U1038, BIG, CEA, Grenoble 38054, France.
Gilles
G
Courtois
Division of Nephrology and Hypertension, Christian-Albrechts-University, Kiel 24105, Germany.
Andreas
0000-0001-6287-9725
A
Linkermann
Division of Nephrology and Hypertension, Christian-Albrechts-University, Kiel 24105, Germany.
Stefan
S
Krautwald
Department of Visceral and Transplantation Surgery, University Hospital RWTH Aachen, Aachen 52074, Germany.
Ulf P
UP
Neumann
Department of Medicine III, University Hospital RWTH Aachen, Aachen 52074, Germany.
Frank
F
Tacke
Department of Medicine III, University Hospital RWTH Aachen, Aachen 52074, Germany.
Christian
C
Trautwein
Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Douglas R
DR
Green
Institute of Pathology, University Hospital RWTH Aachen, Aachen 52074, Germany.
Thomas
T
Longerich
Department of Cardiology and Angiology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel 24105, Germany.
Norbert
N
Frey
Department of Cardiology and Angiology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel 24105, Germany.
Mark
M
Luedde
Department of Medicine, University of Leipzig, Leipzig 04103, Germany.
Matthias
M
Bluher
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.|German Center for Diabetes Research (DZD), Neuherberg 85764, Germany.
Stephan
S
Herzig
Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
Mathias
M
Heikenwalder
Department of Medicine III, University Hospital RWTH Aachen, Aachen 52074, Germany.|Division of GI and Hepatobiliary Oncology, University Hospital RWTH Aachen, Aachen 52074, Germany.
Tom
T
Luedde
D017667:Adipocytes / Q000201:enzymology / Q000473:pathology; D052436:Adipose Tissue, White / Q000201:enzymology* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015992:Body Mass Index; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D002794:Choline / Q000378:metabolism; D002796:Choline Deficiency / Q000201:enzymology / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D059305:Diet, High-Fat; D005786:Gene Expression Regulation; D018149:Glucose Intolerance / Q000201:enzymology / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D006706:Homeostasis; D006801:Humans; D007249:Inflammation; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D009336:Necrosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009765:Obesity / Q000201:enzymology / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism
D007328:Insulin; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; C505526:Casp8 protein, mouse; D053181:Caspase 8; D002794:Choline