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

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Birgitte Lindegaard Madsen, Vance B Matthews, Claus Brandt, Pernille Hojman, Tamara L. Allen, Emma Estevez, Matthew J. Watt, Clinton R. Bruce, Ole Hartvig 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

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.
Original languageEnglish
JournalDiabetes
Volume62
Issue number9
Pages (from-to)3064-3074
Number of pages11
ISSN0012-1797
DOIs
StatePublished - 2013

ID: 47257355