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

Elaine Xu, Mafalda M. A. Pereira, Ismene Karakasilioti, Sebastian Theurich, Mona Al-Maarri, Gunter Rappl, Ari Waisman, F. Thomas Wunderlich and Jens C. Brüning ()
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Elaine Xu: Max Planck Institute for Metabolism Research
Mafalda M. A. Pereira: Max Planck Institute for Metabolism Research
Ismene Karakasilioti: Max Planck Institute for Metabolism Research
Sebastian Theurich: Max Planck Institute for Metabolism Research
Mona Al-Maarri: Max Planck Institute for Metabolism Research
Gunter Rappl: University of Cologne
Ari Waisman: Institute for Molecular Medicine, University of Medical Centre of the Johannes Gutenberg University of Mainz
F. Thomas Wunderlich: Max Planck Institute for Metabolism Research
Jens C. Brüning: Max Planck Institute for Metabolism Research

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: Abstract 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-6RαT-KO) 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-6RαT-KO 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.

Date: 2017
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DOI: 10.1038/ncomms14803

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