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

Birgitte Lindegaard Madsen; Vance B Matthews; Claus Brandt; Pernille Hojman; Tamara L. Allen; Emma Estevez; Matthew J. Watt; Clinton R. Bruce; Ole Hartvig Mortensen; Susanne Syberg; Caroline Rudnicka; Julie Abildgaard; Henriette Pilegaard; Juan Hidalgo; Susanne Ditlevsen; Thomas J Alsted; Andreas N Madsen; Bente K Pedersen; Mark A Febbraio

doi:10.2337/db12-1095

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

Birgitte Lindegaard Madsen, Vance B Matthews, Claus Brandt, Pernille Hojman, Tamara L. Allen, Emma Estevez, Matthew J. Watt, Clinton R. Bruce, Ole Hartvig Mortensen, Susanne Syberg, Caroline Rudnicka, Julie Abildgaard, Henriette Pilegaard, Juan Hidalgo, Susanne Ditlevsen, Thomas J Alsted, Andreas N Madsen, Bente K Pedersen, Mark A Febbraio

49 Citations (Scopus)

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 a-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 language	English
Journal	Diabetes
Volume	62
Issue number	9
Pages (from-to)	3064-3074
Number of pages	11
ISSN	0012-1797
DOIs	https://doi.org/10.2337/db12-1095
Publication status	Published - Sept 2013

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Madsen, B. L., Matthews, V. B., 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. (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

Madsen, BL, Matthews, VB, 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

@article{e0a223923d2a41ac9138e359857f5d40,

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 a-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.",

author = "Madsen, {Birgitte Lindegaard} and Matthews, {Vance B} and Claus Brandt and Pernille Hojman and Allen, {Tamara L.} and Emma Estevez and Watt, {Matthew J.} and Bruce, {Clinton R.} and Mortensen, {Ole Hartvig} and Susanne Syberg and Caroline Rudnicka and Julie Abildgaard and Henriette Pilegaard and Juan Hidalgo and Susanne Ditlevsen and Alsted, {Thomas J} and Madsen, {Andreas N} and Pedersen, {Bente K} and Febbraio, {Mark A}",

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doi = "10.2337/db12-1095",

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pages = "3064--3074",

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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 - 2013/9

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 a-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 a-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 - Journal article

C2 - 23670974

SN - 0012-1797

VL - 62

SP - 3064

EP - 3074

JO - Diabetes

JF - Diabetes

IS - 9

ER -

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

Abstract

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