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

Nat Commun. 2017 May 3:8:14803. doi: 10.1038/ncomms14803.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Diet, High-Fat
  • Homeostasis
  • Inflammation / metabolism*
  • Insulin Resistance*
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism*
  • Lipid Metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Obesity / metabolism*
  • Receptors, Interleukin-6 / genetics
  • Signal Transduction*
  • T-Lymphocytes / metabolism*
  • Time Factors

Substances

  • Blood Glucose
  • Interleukin-6
  • Receptors, Interleukin-6
  • interleukin-6 receptor alpha