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

被引：69

作者：

Gautheron, Jeremie ^{[1
,2
]}

Vucur, Mihael ^{[1
,2
]}

Schneider, Anne T. ^{[1
,2
]}

Severi, Ilenia ^{[3
]}

Roderburg, Christoph ^{[1
]}

Roy, Sanchari ^{[1
,2
]}

Bartneck, Matthias ^{[1
]}

Schrammen, Peter ^{[1
]}

Diaz, Mauricio Berriel ^{[4
,5
,6
]}

Ehling, Josef ^{[7
,8
]}

Gremse, Felix ^{[7
,8
]}

Heymann, Felix ^{[1
]}

Koppe, Christiane ^{[1
,2
]}

Lammers, Twan ^{[7
,8
]}

Kiessling, Fabian ^{[7
,8
]}

Van Best, Niels ^{[9
]}

Pabst, Oliver ^{[9
]}

Courtois, Gilles ^{[10
]}

Linkermann, Andreas ^{[11
]}

Krautwald, Stefan ^{[11
]}

Neumann, Ulf P. ^{[12
]}

Tacke, Frank ^{[1
]}

Trautwein, Christian ^{[1
]}

Green, Douglas R. ^{[13
]}

Longerich, Thomas ^{[14
]}

Frey, Norbert ^{[15
]}

Luedde, Mark ^{[15
]}

Bluher, Matthias ^{[16
]}

Herzig, Stephan ^{[4
,5
,6
,17
]}

Heikenwalder, Mathias ^{[18
]}

Luedde, Tom ^{[1
,2
]}

机构：

[1] Univ Hosp RWTH Aachen, Dept Med 3, D-52074 Aachen, Germany

[2] Univ Hosp RWTH Aachen, Div GI & Hepatobiliary Oncol, D-52074 Aachen, Germany

[3] Univ Ancona, Dept Expt & Clin Med, I-60020 Ancona, Italy

[4] Inst Diabet Endocrinol & Metab Dis, D-85764 Neuherberg, Germany

[5] Canc IDC Helmholtz Ctr Munich, D-85764 Neuherberg, Germany

[6] Heidelberg Univ, Joint Heidelberg IDC Translat Diabet Program, Inner Med 1, D-69120 Heidelberg, Germany

[7] Rhein Westfal TH Aachen, Univ Clin, Dept Expt Mol Imaging, D-52074 Aachen, Germany

[8] Rhein Westfal TH Aachen, Helmholtz Inst Biomed Engn, D-52074 Aachen, Germany

[9] Univ Hosp RWTH Aachen, Inst Med Microbiol, D-52074 Aachen, Germany

[10] CEA, BIG, Inserm U1038, F-38054 Grenoble, France

[11] Univ Kiel, Div Nephrol & Hypertens, D-24105 Kiel, Germany

[12] Univ Hosp RWTH Aachen, Dept Visceral & Transplantat Surg, D-52074 Aachen, Germany

[13] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA

[14] Univ Hosp RWTH Aachen, Inst Pathol, D-52074 Aachen, Germany

[15] Univ Hosp Schleswig Holstein, Dept Cardiol & Angiol, Campus Kiel, D-24105 Kiel, Germany

[16] Univ Leipzig, Dept Med, D-04103 Leipzig, Germany

[17] German Ctr Diabet Res DZD, D-85764 Neuherberg, Germany

[18] German Canc Res Ctr, Div Chron Inflammat & Canc, D-69120 Heidelberg, Germany

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

关键词：

TUMOR-NECROSIS-FACTOR; MIXED LINEAGE KINASE; INSULIN-RESISTANCE; CELL-DEATH; ADIPOCYTE APOPTOSIS; FATTY LIVER; OBESITY; MACROPHAGES; RECEPTORS; CANCER;

D O I：

10.1038/ncomms11869

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：16

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