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

Jeremie 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

Jeremie 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 KrautwaldUlf P. Neumann, Frank Tacke, Christian Trautwein, Douglas R. Green, Thomas Longerich, Norbert Frey, Mark Luedde, Matthias Bluher, Stephan Herzig, Mathias Heikenwalder, Tom Luedde^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Article number	11869
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms11869
Publication status	Published - Jun 2016

Access to Document

10.1038/ncomms11869Licence: CC BY

Cite this

Gautheron, J., Vucur, M., Schneider, A. T., Severi, I., Roderburg, C., Roy, S., Bartneck, M., Schrammen, P., Diaz, M. B., Ehling, J., Gremse, F., Heymann, F., Koppe, C., Lammers, T., Kiessling, F., Van Best, N., Pabst, O., Courtois, G., Linkermann, A., ... Luedde, T. (2016). The necroptosis-inducing kinase RIPK3 dampens adipose tissue inflammation and glucose intolerance. Nature Communications, 7, Article 11869. https://doi.org/10.1038/ncomms11869

@article{280ef06e6cee4858b5a6d9cd7173eea1,

title = "The necroptosis-inducing kinase RIPK3 dampens adipose tissue inflammation and glucose intolerance",

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.",

author = "Jeremie Gautheron and Mihael Vucur and Schneider, {Anne T.} and Ilenia Severi and Christoph Roderburg and Sanchari Roy and Matthias Bartneck and Peter Schrammen and Diaz, {Mauricio Berriel} and Josef Ehling and Felix Gremse and Felix Heymann and Christiane Koppe and Twan Lammers and Fabian Kiessling and {Van Best}, Niels and Oliver Pabst and Gilles Courtois and Andreas Linkermann and Stefan Krautwald and Neumann, {Ulf P.} and Frank Tacke and Christian Trautwein and Green, {Douglas R.} and Thomas Longerich and Norbert Frey and Mark Luedde and Matthias Bluher and Stephan Herzig and Mathias Heikenwalder and Tom Luedde",

year = "2016",

month = jun,

doi = "10.1038/ncomms11869",

language = "English",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Gautheron, J, Vucur, M, Schneider, AT, Severi, I, Roderburg, C, Roy, S, Bartneck, M, Schrammen, P, Diaz, MB, Ehling, J, Gremse, F, Heymann, F, Koppe, C, Lammers, T, Kiessling, F, Van Best, N, Pabst, O, Courtois, G, Linkermann, A, Krautwald, S, Neumann, UP, Tacke, F, Trautwein, C, Green, DR, Longerich, T, Frey, N, Luedde, M, Bluher, M, Herzig, S, Heikenwalder, M & Luedde, T 2016, 'The necroptosis-inducing kinase RIPK3 dampens adipose tissue inflammation and glucose intolerance', Nature Communications, vol. 7, 11869. https://doi.org/10.1038/ncomms11869

TY - JOUR

T1 - The necroptosis-inducing kinase RIPK3 dampens adipose tissue inflammation and glucose intolerance

AU - Gautheron, Jeremie

AU - Vucur, Mihael

AU - Schneider, Anne T.

AU - Severi, Ilenia

AU - Roderburg, Christoph

AU - Roy, Sanchari

AU - Bartneck, Matthias

AU - Schrammen, Peter

AU - Diaz, Mauricio Berriel

AU - Ehling, Josef

AU - Gremse, Felix

AU - Heymann, Felix

AU - Koppe, Christiane

AU - Lammers, Twan

AU - Kiessling, Fabian

AU - Van Best, Niels

AU - Pabst, Oliver

AU - Courtois, Gilles

AU - Linkermann, Andreas

AU - Krautwald, Stefan

AU - Neumann, Ulf P.

AU - Tacke, Frank

AU - Trautwein, Christian

AU - Green, Douglas R.

AU - Longerich, Thomas

AU - Frey, Norbert

AU - Luedde, Mark

AU - Bluher, Matthias

AU - Herzig, Stephan

AU - Heikenwalder, Mathias

AU - Luedde, Tom

PY - 2016/6

Y1 - 2016/6

N2 - 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.

AB - 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.

U2 - 10.1038/ncomms11869

DO - 10.1038/ncomms11869

M3 - Article

C2 - 27323669

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 11869

ER -