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

Mihai G Netea; Leo A B Joosten; Eli Lewis; Dalan R Jensen; Peter J Voshol; Bart Jan Kullberg; Cees J Tack; Han van Krieken; Soo-Hyun Kim; Anton F Stalenhoef; Fons A van de Loo; Ineke Verschueren; Leslie Pulawa; Shizuo Akira; Robert H Eckel; Charles A Dinarello; Wim van den Berg; Jos W M van der Meer

doi:10.1038/nm1415

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

Nat Med. 2006 Jun;12(6):650-6. doi: 10.1038/nm1415. Epub 2006 May 28.

Authors

Mihai G Netea¹, Leo A B Joosten, Eli Lewis, Dalan R Jensen, Peter J Voshol, Bart Jan Kullberg, Cees J Tack, Han van Krieken, Soo-Hyun Kim, Anton F Stalenhoef, Fons A van de Loo, Ineke Verschueren, Leslie Pulawa, Shizuo Akira, Robert H Eckel, Charles A Dinarello, Wim van den Berg, Jos W M van der Meer

Affiliation

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

PMID: 16732281
DOI: 10.1038/nm1415

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Body Weight
Eating
Energy Metabolism
Gluconeogenesis / physiology
Glucose / metabolism
Glycoproteins / genetics
Glycoproteins / metabolism
Homeostasis
Hyperphagia* / genetics
Hyperphagia* / metabolism
Insulin Resistance* / genetics
Insulin Resistance* / physiology
Intercellular Signaling Peptides and Proteins
Interleukin-18 / deficiency*
Interleukin-18 / genetics
Interleukin-18 Receptor alpha Subunit
Liver / physiology
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Obesity* / genetics
Obesity* / metabolism
Receptors, Interleukin / genetics
Receptors, Interleukin / metabolism
Receptors, Interleukin-18
Recombinant Proteins / genetics
Recombinant Proteins / metabolism
STAT3 Transcription Factor / metabolism

Substances

Glycoproteins
Il18r1 protein, mouse
Intercellular Signaling Peptides and Proteins
Interleukin-18
Interleukin-18 Receptor alpha Subunit
Receptors, Interleukin
Receptors, Interleukin-18
Recombinant Proteins
STAT3 Transcription Factor
Stat3 protein, mouse
interleukin-18 binding protein
Glucose