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Article
Nature Medicine - 12, 650 - 656 (2006)
Published online: 28 May 2006; | doi:10.1038/nm1415

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

Mihai G Netea1, 2, 8, Leo A B Joosten3, 8, Eli Lewis2, Dalan R Jensen4, Peter J Voshol5, Bart Jan Kullberg1, Cees J Tack1, Han van Krieken6, Soo-Hyun Kim3, Anton F Stalenhoef1, Fons A van de Loo3, Ineke Verschueren1, Leslie Pulawa4, Shizuo Akira7, Robert H Eckel4, Charles A Dinarello2, Wim van den Berg3 & Jos W M van der Meer1

1  Department of Internal Medicine and Nijmegen University Center for Infectious Diseases, Geert Grooteplein 8, 6500 HB, Nijmegen, The Netherlands.

2  Division of Infectious Diseases University of Colorado Health Sciences Center, 4200 East Ninth Avenue, B168, Denver, Colorado 80262, USA.

3  Department of Rheumatology Research and Advanced Therapeutics, Nijmegen Center for Molecular Life Sciences, Radboud University Nijmegen Medical Center, Geert Grooteplein 22, 6500 HB Nijmegen, The Netherlands.

4  Division of Endocrinology, Fitzsimmons Campus RC-1 South, P.O. Box 6511, MS 8106, Aurora, Colorado 80045, University of Colorado Health Sciences Center, USA.

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

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

7  Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Yamadaoka 3-1, Suita, Osaka 565-0871, Japan.

8  These authors contributed equally to this work.

Correspondence should be addressed to Mihai G Netea m.netea@aig.umcn.nl

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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Nature Medicine
ISSN: 1078-8956
EISSN: 1546-170X
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