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

Birgitte Lindegaard, Vance B Matthews, Claus Brandt, Pernille Hojman, Tamara L Allen, Emma Estevez, Matthew J Watt, Clinton R Bruce, Ole H Mortensen, Susanne Syberg, Caroline Rudnicka, Julie Abildgaard, Henriette Pilegaard, Juan Hidalgo, Susanne Ditlevsen, Thomas Junker Alsted, Andreas Madsen, Bente K Pedersen, Mark A Febbraio

    65 Citations (Scopus)


    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.
    Original languageEnglish
    Issue number9
    Pages (from-to)3064-74
    Number of pages11
    Publication statusPublished - Sep 2013


    • AMP-Activated Protein Kinases
    • Animals
    • Body Composition
    • Calorimetry, Indirect
    • Female
    • Insulin Resistance
    • Interleukin-18
    • Male
    • Mice
    • Mice, Inbred C57BL
    • Mice, Knockout
    • Muscle, Skeletal
    • Real-Time Polymerase Chain Reaction
    • Receptors, Interleukin-18
    • Weight Gain


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