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

• Published in: Nature communications Vol. 7; no. 1; pp. 11869 - 16
• Main Authors: Gautheron, Jérémie, Vucur, Mihael, Schneider, Anne T., Severi, Ilenia, Roderburg, Christoph, Roy, Sanchari, Bartneck, Matthias, Schrammen, Peter, Diaz, Mauricio Berriel, Ehling, Josef, Gremse, Felix, Heymann, Felix, Koppe, Christiane, Lammers, Twan, Kiessling, Fabian, Van Best, Niels, Pabst, Oliver, Courtois, Gilles, Linkermann, Andreas, Krautwald, Stefan, Neumann, Ulf P., Tacke, Frank, Trautwein, Christian, Green, Douglas R., Longerich, Thomas, Frey, Norbert, Luedde, Mark, Bluher, Matthias, Herzig, Stephan, Heikenwalder, Mathias, Luedde, Tom
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.06.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/2; 13/31; 14/1; 14/28; 14/63; 38/77; 59/57; 631/250/256; 631/443/319/1557; 631/45/607/275; 631/80/82/2344; 64/60; 82/29; 82/80; 96/21; 96/31; 96/95; Adipocytes - enzymology; Adipocytes - pathology; Adipose Tissue, White - enzymology; Adipose Tissue, White - pathology; Animals; Apoptosis - genetics; Biochemistry, Molecular Biology; Body fat; 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; Endocrinology and metabolism; Gene Expression Regulation; Glucose Intolerance - enzymology; Glucose Intolerance - etiology; Glucose Intolerance - genetics; Glucose Intolerance - pathology; Homeostasis; Human health and pathology; Humanities and Social Sciences; Humans; Inflammation; Insulin - metabolism; Insulin Resistance; Intra-Abdominal Fat - enzymology; Intra-Abdominal Fat - pathology; Kinases; Life Sciences; Male; Mice; multidisciplinary; Necrosis - enzymology; Necrosis - genetics; Necrosis - pathology; Obesity; Obesity - enzymology; Obesity - etiology; Obesity - genetics; Obesity - pathology; Receptor-Interacting Protein Serine-Threonine Kinases - genetics; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Science; Science (multidisciplinary); Aachen Germany; Germany
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms11869

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. The kinase RIPK3 initiates necroptosis, which has been reported to promote inflammation in various pathological conditions. Here, the authors show that genetic ablation of Ripk3 results in adipocyte apoptosis and white adipose tissue inflammation in obese mice, which promotes glucose intolerance.