Interleukin-18 Activates Skeletal Muscle AMPK and Reduces Weight Gain and Insulin Resistance in Mice

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Lindegaard, B; Matthews, VB; Brandt, C; Hojman, P; Allen, TL; Estevez, E; Watt, MJ; Bruce, CR; Mortensen, OH; Syberg, S; ...Date
2013-09-01Source Title
DiabetesPublisher
AMER DIABETES ASSOCUniversity of Melbourne Author/s
Watt, MatthewAffiliation
PhysiologyMetadata
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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 (9), pp.3064-3074. https://doi.org/10.2337/db12-1095.Access Status
Open AccessAbstract
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.
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