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, Copenhagen, Denmark
  2. 2Department of Infectious Diseases, University of Copenhagen, Copenhagen, Denmark
  3. 3Department of Biology, University of Copenhagen, Copenhagen, Denmark
  4. 4Department of Mathematical Sciences, University of Copenhagen, Copenhagen, Denmark
  5. 5Department of Physiology, University of Copenhagen, Copenhagen, Denmark
  6. 6Department of Molecular Pharmacology, University of Copenhagen, Copenhagen, Denmark
  7. 7Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Australia
  8. 8University of Western Australia 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, Hvidovre, 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}, or Bente K. Pedersen, bente.klarlund.pedersen{at}


Circulating interleukin (IL)-18 is elevated in obesity, but paradoxically causes hypophagia. We hypothesized that IL-18 may attenuate high-fat diet (HFD)-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 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, 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 HFD-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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