Circulating interleukin (IL)-18 is elevated in obesity, but paradoxically causes hypophagia. We hypothesized that IL-18 may attenuate high fat diet 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 high fat diet (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, and 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 high fat diet-induced weight gain. In summary IL-18 enhances AMPK signaling and lipid oxidation in skeletal muscle implicating IL-18 in metabolic homeostasis.
Diabetes, 2013, Vol 62, Issue 9, p. 3064-3074
Journal Article; Research Support, Non-U.S. Gov't; 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