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

B Lindegaard, VB Matthews, C Brandt, P Hojman… - Diabetes, 2013 - Am Diabetes Assoc
B Lindegaard, VB Matthews, C Brandt, P Hojman, TL Allen, E Estevez, MJ Watt, CR Bruce
Diabetes, 2013Am Diabetes Assoc
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 …
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.
Am Diabetes Assoc