Interleukin-18 activates skeletal muscle AMPK and reduces weight gain and insulin resistance in mice

  1. Mark A. Febbraio7,
  1. 1The Centre of Inflammation and Metabolism, Rigshospitalet
  2. Departments of 2Infectious Diseases
  3. 3Biology
  4. 4Mathematical Sciences
  5. 5Physiology
  6. 6Molecular Pharmacology, University of Copenhagen, Denmark
  7. 7Cellular and Molecular Metabolism Laboratory, BakerIDI Heart & Diabetes Institute, Melbourne, Australia
  8. 8UWA Centre for Medical Research, Western Australian Institute for Medical Research, Perth, Australia
  9. 9Department of Physiology, Monash University, Clayton, Australia
  10. 10Osteoporosis Unit, Hvidovre Hospital, Denmark
  11. 11Institute of Neurosciences, Department of Cellular Biology, Physiology and Immunology, Animal Physiology Unit, Faculty of Sciences, Autonomous University of Barcelona, Barcelona, Spain.
  1. Corresponding author: Mark A Febbraio mark.febbraio{at}bakeridi.edu.au

Abstract

Circulating interleukin (IL)-18 is elevated in obesity, but paradoxically causes hypophagia. We hypothesized that IL-18 may attenuate high fat diet induced insulin resistance by activating AMP activated protein kinase (AMPK). We studied mice with a global deletion of the α isoform of the IL-18 receptor (IL-18R-/-), fed a standard chow or high fat diet (HFD). We next performed gain of function experiments in skeletal muscle, in vitro, ex vivo and in vivo. We show that IL-18 is implicated in metabolic homeostasis, inflammation and insulin resistance via mechanisms involving the activation of AMPK in skeletal muscle. IL-18R-/- mice display increased weight gain, and ectopic lipid deposition, inflammation and reduced AMPK signaling in skeletal muscle. Treating myotubes or skeletal muscle strips with IL-18 activated AMPK and increased fat oxidation. Moreover, in vivo electroporation of IL-18 into skeletal muscle activated AMPK and concomitantly inhibited high fat diet-induced weight gain. In summary IL-18 enhances AMPK signaling and lipid oxidation in skeletal muscle implicating IL-18 in metabolic homeostasis.

  • Received August 14, 2012.
  • Accepted May 7, 2013.

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