Interleukin-18 activates skeletal muscle AMPK and reduces weight gain and insulin resistance in mice
- Birgitte Lindegaard1,2,7,
- Vance B. Matthews7,8,
- Claus Brandt1,
- Pernille Hojman1,
- Tamara L. Allen7,
- Emma Estevez7,
- Matthew J. Watt9,
- Clinton R. Bruce7,9,
- Ole Mortensen1,
- Susanne Syberg1,10,
- Caroline Rudnicka8,
- Julie Abildgaard1,
- Henriette Pilegaard1,3,
- Juan Hidalgo11,
- Susanne Ditlevsen4,
- Thomas J. Alsted5,
- Andreas N. Madsen6,
- Bente K. Pedersen1 and
- Mark A. Febbraio7,†
- 1The Centre of Inflammation and Metabolism, Rigshospitalet
- Departments of 2Infectious Diseases
- 4Mathematical Sciences
- 6Molecular Pharmacology, University of Copenhagen, Denmark
- 7Cellular and Molecular Metabolism Laboratory, BakerIDI Heart & Diabetes Institute, Melbourne, Australia
- 8UWA Centre for Medical Research, Western Australian Institute for Medical Research, Perth, Australia
- 9Department of Physiology, Monash University, Clayton, Australia
- 10Osteoporosis Unit, Hvidovre Hospital, Denmark
- 11Institute of Neurosciences, Department of Cellular Biology, Physiology and Immunology, Animal Physiology Unit, Faculty of Sciences, Autonomous University of Barcelona, Barcelona, Spain.
- †Corresponding author: Mark A Febbraio
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.
- © 2013 by the American Diabetes Association.
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