Interleukin-18 activates skeletal muscle AMPK and reduces weight gain and insulin resistance in mice
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Interleukin-18 activates skeletal muscle AMPK and reduces weight gain and insulin resistance in mice. / Madsen, Birgitte Lindegaard; Matthews, Vance B; Brandt, Claus; Hojman, Pernille; Allen, Tamara L.; Estevez, Emma; Watt, Matthew J.; Bruce, Clinton R.; Mortensen, Ole Hartvig; Syberg, Susanne; Rudnicka, Caroline; Abildgaard, Julie; Pilegaard, Henriette; Hidalgo, Juan; Ditlevsen, Susanne; Alsted, Thomas J; Madsen, Andreas N; Pedersen, Bente K; Febbraio, Mark A.
I: Diabetes, Bind 62, Nr. 9, 2013, s. 3064-3074.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Interleukin-18 activates skeletal muscle AMPK and reduces weight gain and insulin resistance in mice
AU - Madsen, Birgitte Lindegaard
AU - Matthews, Vance B
AU - Brandt, Claus
AU - Hojman, Pernille
AU - Allen, Tamara L.
AU - Estevez, Emma
AU - Watt, Matthew J.
AU - Bruce, Clinton R.
AU - Mortensen, Ole Hartvig
AU - Syberg, Susanne
AU - Rudnicka, Caroline
AU - Abildgaard, Julie
AU - Pilegaard, Henriette
AU - Hidalgo, Juan
AU - Ditlevsen, Susanne
AU - Alsted, Thomas J
AU - Madsen, Andreas N
AU - Pedersen, Bente K
AU - Febbraio, Mark A
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
U2 - 10.2337/db12-1095
DO - 10.2337/db12-1095
M3 - Journal article
C2 - 23670974
VL - 62
SP - 3064
EP - 3074
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 9
ER -
ID: 47257355