Interleukin-18 Activates Skeletal Muscle AMPK and Reduces Weight Gain and Insulin Resistance in Mice

B. Lindegaard, Vance Matthews, C. Brandt, P. Hojman, T.L. Allen, E. Estevez, M.J. Watt, C.R. Bruce, O.H. Mortensen, S. Syberg, C. Rudnicka, J. Abildgaard, H. Pilegaard, J. Hidalgo, S. Ditlevsen, T.J. Alsted, A.N. Madsen, B.K. Pedersen, M.A. Febbraio

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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.
Original languageEnglish
Pages (from-to)3064-3074
JournalDiabetes
Volume62
Issue number9
Early online date13 May 2013
DOIs
Publication statusPublished - Sep 2013

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AMP-Activated Protein Kinases
Interleukin-18
Weight Gain
Insulin Resistance
Skeletal Muscle
High Fat Diet
Interleukin-18 Receptors
Homeostasis
Inflammation
Lipids
Electroporation
Interleukins
Skeletal Muscle Fibers
Protein Isoforms
Obesity
Fats

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Lindegaard, B., Matthews, V., Brandt, C., Hojman, P., Allen, T. L., Estevez, E., ... Febbraio, M. A. (2013). Interleukin-18 Activates Skeletal Muscle AMPK and Reduces Weight Gain and Insulin Resistance in Mice. Diabetes, 62(9), 3064-3074. https://doi.org/10.2337/db12-1095
Lindegaard, B. ; Matthews, Vance ; Brandt, C. ; Hojman, P. ; Allen, T.L. ; Estevez, E. ; Watt, M.J. ; Bruce, C.R. ; Mortensen, O.H. ; Syberg, S. ; Rudnicka, C. ; Abildgaard, J. ; Pilegaard, H. ; Hidalgo, J. ; Ditlevsen, S. ; Alsted, T.J. ; Madsen, A.N. ; Pedersen, B.K. ; Febbraio, M.A. / Interleukin-18 Activates Skeletal Muscle AMPK and Reduces Weight Gain and Insulin Resistance in Mice. In: Diabetes. 2013 ; Vol. 62, No. 9. pp. 3064-3074.
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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.",
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Lindegaard, B, Matthews, V, 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 2013, 'Interleukin-18 Activates Skeletal Muscle AMPK and Reduces Weight Gain and Insulin Resistance in Mice' Diabetes, vol. 62, no. 9, pp. 3064-3074. https://doi.org/10.2337/db12-1095

Interleukin-18 Activates Skeletal Muscle AMPK and Reduces Weight Gain and Insulin Resistance in Mice. / Lindegaard, B.; Matthews, Vance; Brandt, C.; Hojman, P.; Allen, T.L.; Estevez, E.; Watt, M.J.; Bruce, C.R.; Mortensen, O.H.; Syberg, S.; Rudnicka, C.; Abildgaard, J.; Pilegaard, H.; Hidalgo, J.; Ditlevsen, S.; Alsted, T.J.; Madsen, A.N.; Pedersen, B.K.; Febbraio, M.A.

In: Diabetes, Vol. 62, No. 9, 09.2013, p. 3064-3074.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Interleukin-18 Activates Skeletal Muscle AMPK and Reduces Weight Gain and Insulin Resistance in Mice

AU - Lindegaard, B.

AU - Matthews, Vance

AU - Brandt, C.

AU - Hojman, P.

AU - Allen, T.L.

AU - Estevez, E.

AU - Watt, M.J.

AU - Bruce, C.R.

AU - Mortensen, O.H.

AU - Syberg, S.

AU - Rudnicka, C.

AU - Abildgaard, J.

AU - Pilegaard, H.

AU - Hidalgo, J.

AU - Ditlevsen, S.

AU - Alsted, T.J.

AU - Madsen, A.N.

AU - Pedersen, B.K.

AU - Febbraio, M.A.

PY - 2013/9

Y1 - 2013/9

N2 - 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.

AB - 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.

U2 - 10.2337/db12-1095

DO - 10.2337/db12-1095

M3 - Article

VL - 62

SP - 3064

EP - 3074

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 9

ER -