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 J. Alsted, Andreas N. Madsen, Bente K. Pedersen, Mark A. Febbraio

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Abstract

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 a-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. © 2013 by the American Diabetes Association.
Original languageEnglish
Pages (from-to)3064-3074
JournalDiabetes
Volume62
DOIs
Publication statusPublished - 1 Sep 2013

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    Lindegaard, B., Matthews, V. B., Brandt, C., Hojman, P., Allen, T. L., Estevez, E., Watt, M. J., Bruce, C. R., Mortensen, O. H., Syberg, S., Rudnicka, C., Abildgaard, J., Pilegaard, H., Hidalgo, J., Ditlevsen, S., Alsted, T. J., Madsen, A. N., Pedersen, B. K., & Febbraio, M. A. (2013). Interleukin-18 activates skeletal muscle AMPK and reduces weight gain and insulin resistance in mice. Diabetes, 62, 3064-3074. https://doi.org/10.2337/db12-1095