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|28||Interleukin-18 activates skeletal muscle AMPK and reduces weight gain and insulin resistance in mice.|
Lindegaard B; Matthews VB; Brandt C; Hojman P; Allen TL; Estevez E; Watt MJ; Bruce CR; Mortensen OH; Syberg S; Rudnicka C; Abildgaard J; Pilegaard H; Hidalgo J; Ditlevsen S; Alsted TJ; Madsen AN; Pedersen BK; Febbraio MA
Diabetes 2013; 62(9): 3064-74
PubMed ID: 23670974
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 alpha-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. Lindegaard, Birgitte