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

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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
JournalDiabetes
Volume62
Issue number9
Pages (from-to)3064-74
Number of pages11
ISSN0012-1797
DOIs
Publication statusPublished - Sep 2013

    Research areas

  • 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

ID: 43146482