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

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

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69 Citations (Scopus)


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 alpha 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.
Original languageEnglish
Pages (from-to)3064 - 3074
Number of pages11
Issue number9
Publication statusPublished - 2013

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