Interleukin-18 Activates Skeletal Muscle AMPK and Reduces Weight Gain and Insulin Resistance in Mice
- Birgitte Lindegaard1,2,7,
- Vance B. Matthews7,8,
- Claus Brandt1,2,
- Pernille Hojman1,2,
- Tamara L. Allen7,
- Emma Estevez7,
- Matthew J. Watt9,
- Clinton R. Bruce7,9,
- Ole H. Mortensen1,2,
- Susanne Syberg1,10,
- Caroline Rudnicka8,
- Julie Abildgaard1,
- Henriette Pilegaard1,3,
- Juan Hidalgo11,
- Susanne Ditlevsen4,
- Thomas J. Alsted5,
- Andreas N. Madsen6,
- Bente K. Pedersen1,2 and
- Mark A. Febbraio7⇑
- 1The Centre of Inflammation and Metabolism, Rigshospitalet, Copenhagen, Denmark
- 2Department of Infectious Diseases, University of Copenhagen, Copenhagen, Denmark
- 3Department of Biology, University of Copenhagen, Copenhagen, Denmark
- 4Department of Mathematical Sciences, University of Copenhagen, Copenhagen, Denmark
- 5Department of Physiology, University of Copenhagen, Copenhagen, Denmark
- 6Department of Molecular Pharmacology, University of Copenhagen, Copenhagen, Denmark
- 7Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Australia
- 8University of Western Australia Centre for Medical Research, Western Australian Institute for Medical Research, Perth, Australia
- 9Department of Physiology, Monash University, Clayton, Australia
- 10Osteoporosis Unit, Hvidovre Hospital, Hvidovre, 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, , or Bente K. Pedersen, .
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-1095/-/DC1.
- Received August 14, 2012.
- Accepted May 7, 2013.
- © 2013 by the American Diabetes Association.
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