Interleukin-18 Activates Skeletal Muscle AMPK and Reduces Weight Gain and Insulin Resistance in Mice
AuthorLindegaard, B; Matthews, VB; Brandt, C; Hojman, P; Allen, TL; Estevez, E; Watt, MJ; Bruce, CR; Mortensen, OH; Syberg, S; ...
PublisherAMER DIABETES ASSOC
University of Melbourne Author/sWatt, Matthew
Document TypeJournal Article
CitationsLindegaard, 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 StatusOpen Access
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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