title: Interleukin-18 activates skeletal muscle AMPK and reduces weight gain and insulin resistance in mice.
abstract: 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.
authors.affiliation: The Centre of Inflammation and Metabolism, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Lindegaard
authors.forename: Vance B
authors.initials: VB
authors.lastname: Matthews
authors.forename: Claus
authors.initials: C
authors.lastname: Brandt
authors.forename: Pernille
authors.initials: P
authors.lastname: Hojman
authors.forename: Tamara L
authors.initials: TL
authors.lastname: Allen
authors.forename: Emma
authors.initials: E
authors.lastname: Estevez
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Watt
authors.forename: Clinton R
authors.initials: CR
authors.lastname: Bruce
authors.forename: Ole H
authors.initials: OH
authors.lastname: Mortensen
authors.forename: Susanne
authors.initials: S
authors.lastname: Syberg
authors.forename: Caroline
authors.initials: C
authors.lastname: Rudnicka
authors.forename: Julie
authors.initials: J
authors.lastname: Abildgaard
authors.forename: Henriette
authors.initials: H
authors.lastname: Pilegaard
authors.forename: Juan
authors.initials: J
authors.lastname: Hidalgo
authors.forename: Susanne
authors.initials: S
authors.lastname: Ditlevsen
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Alsted
authors.forename: Andreas N
authors.initials: AN
authors.lastname: Madsen
authors.forename: Bente K
authors.initials: BK
authors.lastname: Pedersen
authors.forename: Mark A
authors.initials: MA
authors.lastname: Febbraio
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001823:Body Composition / Q000235:genetics / Q000502:physiology; D002153:Calorimetry, Indirect; D005260:Female; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D020382:Interleukin-18 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000201:enzymology*; D060888:Real-Time Polymerase Chain Reaction; D053724:Receptors, Interleukin-18 / Q000172:deficiency / Q000235:genetics; D015430:Weight Gain / Q000235:genetics / Q000502:physiology*
chemical_list: D020382:Interleukin-18; D053724:Receptors, Interleukin-18; D055372:AMP-Activated Protein Kinases