Temporal and tissue-specific requirements for T-lymphocyte IL-6 signalling in obesity-associated inflammation and insulin resistance

• Published in: Nature communications Vol. 8; no. 1; p. 14803
• Main Authors: Xu, Elaine, Pereira, Mafalda M A, Karakasilioti, Ismene, Theurich, Sebastian, Al-Maarri, Mona, Rappl, Gunter, Waisman, Ari, Wunderlich, F Thomas, Brüning, Jens C
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 03.05.2017; Nature Portfolio
• Subjects: Animals; Blood Glucose - metabolism; Body fat; Cells; Cytokines; Diabetes; Diet, High-Fat; Glucose; Homeostasis; Inflammation - metabolism; Insulin Resistance; Interleukin-6 - genetics; Interleukin-6 - metabolism; Lipid Metabolism; Lymphocytes; Male; Medicine; Metabolism; Mice; Mice, Knockout; Obesity; Obesity - metabolism; Receptors, Interleukin-6 - genetics; Signal Transduction; T-Lymphocytes - metabolism; Time Factors; Germany
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms14803

Low-grade inflammation links obesity to insulin resistance through the activation of tissue-infiltrating immune cells. Interleukin-6 (IL-6) is a crucial regulator of T cells and is increased in obesity. Here we report that classical IL-6 signalling in T cells promotes inflammation and insulin resistance during the first 8 weeks on a high-fat diet (HFD), but becomes dispensable at later stages (after 16 weeks). Mice with T cell-specific deficiency of IL-6 receptor-α (IL-6Rα ) exposed to a HFD display improved glucose tolerance, insulin sensitivity and inflammation in liver and EWAT after 8 weeks. However, after 16 weeks, insulin resistance in IL-6Rα epididymal white adipose tissue (EWAT) is comparable to that of controls, whereas the inflammatory profile is significantly worse. This coincided with a shift from classical T cell IL-6 signalling at 8 weeks, to enhanced IL-6 trans-signalling at 16 weeks. Collectively, our studies reveal that IL-6 action in T cells through classical IL-6 signalling promotes inflammation and insulin resistance early during obesity development, which can be compensated for by enhanced IL-6 trans-signalling at later stages.