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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
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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