Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance (original) (raw)
- Article
- Published: 28 May 2006
- Leo A B Joosten3 na1,
- Eli Lewis2,
- Dalan R Jensen4,5,
- Peter J Voshol6,
- Bart Jan Kullberg1,
- Cees J Tack1,
- Han van Krieken7,
- Soo-Hyun Kim3,
- Anton F Stalenhoef1,
- Fons A van de Loo3,
- Ineke Verschueren1,
- Leslie Pulawa4,5,
- Shizuo Akira8,
- Robert H Eckel4,5,
- Charles A Dinarello2,
- Wim van den Berg3 &
- …
- Jos W M van der Meer1
Nature Medicine volume 12, pages 650–656 (2006)Cite this article
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Abstract
Here we report the presence of hyperphagia, obesity and insulin resistance in knockout mice deficient in IL-18 or IL-18 receptor, and in mice transgenic for expression of IL-18 binding protein. Obesity of _Il18_−/− mice resulted from accumulation of fat tissue based on increased food intake. Il18 −/− mice also had hyperinsulinemia, consistent with insulin resistance and hyperglycemia. Insulin resistance was secondary to obesity induced by increased food intake and occurred at the liver level as well as at the muscle and fat-tissue level. The molecular mechanisms responsible for the hepatic insulin resistance in the Il18 −/− mice involved an enhanced expression of genes associated with gluconeogenesis in the liver of Il18 −/− mice, resulting from defective phosphorylation of STAT3. Recombinant IL-18 (rIL-18) administered intracerebrally inhibited food intake. In addition, rIL-18 reversed hyperglycemia in Il18 −/− mice through activation of STAT3 phosphorylation. These findings indicate a new role of IL-18 in the homeostasis of energy intake and insulin sensitivity.
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Acknowledgements
M.G.N. was supported by a Vidi grant from Netherlands Foundation of Scientific Research (NWO). P.J.V. was supported by Zon-MW Veni grant 916-36-071. We thank G. Fantuzzi for her help with the leptin-resistance experiments, and critically reading the manuscript.
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Author notes
- Mihai G Netea and Leo A B Joosten: These authors contributed equally to this work.
Authors and Affiliations
- Department of Internal Medicine and Nijmegen University Center for Infectious Diseases, Geert Grooteplein 8, Nijmegen, 6500 HB, The Netherlands
Mihai G Netea, Bart Jan Kullberg, Cees J Tack, Anton F Stalenhoef, Ineke Verschueren & Jos W M van der Meer - Division of Infectious Diseases University of Colorado Health Sciences Center, 4200 East Ninth Avenue, B168, Denver, 80262, Colorado, USA
Mihai G Netea, Eli Lewis & Charles A Dinarello - Department of Rheumatology Research and Advanced Therapeutics, Nijmegen Center for Molecular Life Sciences, Radboud University Nijmegen Medical Center, Geert Grooteplein 22, Nijmegen, 6500 HB, The Netherlands
Leo A B Joosten, Soo-Hyun Kim, Fons A van de Loo & Wim van den Berg - Division of Endocrinology, Fitzsimmons Campus RC-1 South, Aurora, P.O. Box 6511, MS 8106, 80045, Colorado
Dalan R Jensen, Leslie Pulawa & Robert H Eckel - University of Colorado Health Sciences Center, USA
Dalan R Jensen, Leslie Pulawa & Robert H Eckel - Department of Endocrinology, Leiden University Medical Center, Albinusdreef 2, ZA Leiden, 2333, The Netherlands
Peter J Voshol - Department of Pathology, Radboud University Nijmegen Medical Center, Geert Grooteplein 10, HB Nijmegen, 6500, The Netherlands
Han van Krieken - Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Yamadaoka 3-1, Suita, Osaka, 565-0871, Japan
Shizuo Akira
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Contributions
M.G.N. and L.A.B.J. designed and performed the experiments, and wrote the manuscript. E.L. designed and performed the experiments, performed statistical analysis and edited the manuscript. D.R.J. and P.J.V. designed and performed experiments and edited the manuscript. B.J.K., C.J.T., A.F.S., R.H.E., C.A.D., W. vd B. and J.W.M. vd M. designed experiments and edited the manuscript. H.v.K., S.-H.K., F.A.v.d.L., I.V. and L.P. performed experiments and edited the manuscript. S.A. provided knockout mice and edited the manuscript.
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Correspondence toMihai G Netea.
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Netea, M., Joosten, L., Lewis, E. et al. Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance.Nat Med 12, 650–656 (2006). https://doi.org/10.1038/nm1415
- Received: 18 January 2006
- Accepted: 25 April 2006
- Published: 28 May 2006
- Issue Date: 01 June 2006
- DOI: https://doi.org/10.1038/nm1415