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Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance

Nature Medicine volume 12, pages 650–656 (2006)Cite this article

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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Figure 1: Il18−/− mice develop spontaneous obesity and diabetes mellitus.
Figure 2: The IL-18 pathway is necessary for a normal glucose tolerance.
Figure 3: Recombinant IL-18 reduced glucose concentrations during the rebound phase of an insulin-tolerance test.
Figure 4: Expression in the liver of genes involved in gluconeogenesis and modulation of glucose metabolism through STAT3-dependent mechanisms by IL-18.

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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

  1. Mihai G Netea and Leo A B Joosten: These authors contributed equally to this work.

Authors and Affiliations

  1. 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

  2. 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

  3. 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

  4. 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

  5. University of Colorado Health Sciences Center, USA

    Dalan R Jensen, Leslie Pulawa & Robert H Eckel

  6. Department of Endocrinology, Leiden University Medical Center, Albinusdreef 2, ZA Leiden, 2333, The Netherlands

    Peter J Voshol

  7. Department of Pathology, Radboud University Nijmegen Medical Center, Geert Grooteplein 10, HB Nijmegen, 6500, The Netherlands

    Han van Krieken

  8. 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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  1. Mihai G Netea
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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.

Corresponding author

Correspondence to Mihai G Netea.

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The authors declare no competing financial interests.

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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

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