Cited by 424Regulation of Appetite and ObesityAdipokines, Inflammation, and Metabolic DiseasesCytokine Signaling Pathways and Interactions

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

Netea, Mihai G, Joosten, Leo A B, Lewis, Eli, Jensen, Dalan R, Voshol, Peter J, Kullberg, Bart Jan, Tack, Cees J, van Krieken, Han +10 more·2006·Nature Medicine

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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Crossref · 10.1038/nm1415

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  • Local production of inflammatory molecules by adipose tissue within the heart may contribute to coronary pathologies because of its amount and proximity to coronary vessels.

    “In this regard, the local production of the inflammatory molecules by adipose tissue within the heart may be important; the amount of this tissue and its proximity to the coronary vessels could contribute to the development of coronary pathologies (60,61) .”

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Authors
Netea, M. G., Joosten, L. A. B., Lewis, E., Jensen, D. R., Voshol, P. J., Kullberg, B. J., Tack, C. J., van Krieken, H., Kim, S.-H., Stalenhoef, A. F., van de Loo, F. A., Verschueren, I., Pulawa, L., Akira, S., Eckel, R. H., Dinarello, C. A., van den Berg, W., & van der Meer, J. W. M.
Affiliations
  • Radboud University Nijmegen (NL)
  • University of Colorado Denver (US)
  • University of Colorado Health (US)
  • Leiden University Medical Center (NL)
  • Research Institute for Microbial Diseases, The University of Osaka (JP)
Corresponding author
Netea, Mihai G
Venue
Nature Medicine
Published
2006-05-28
Volume
12
Issue
6
Pages
650-656
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
OpenAlex
W2117361576
Cited by
424
References
25
Citations by year
2026: 11 · 2025: 21 · 2024: 17 · 2023: 12 · 2022: 15 · 2021: 18 · 2020: 18 · 2019: 23 · 2018: 30 · 2017: 16 · 2016: 24 · 2015: 27 · 2014: 20 · 2013: 38 · 2012: 27
FWCI
9.25
Type
journal article
Language
en
Open access
closed
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Radboud Repository (Radboud University) (submittedVersion)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Keywords
IL-18, IL-18 receptor, IL-18 binding protein, hyperphagia, obesity, insulin resistance, hyperinsulinemia, hyperglycemia, hepatic insulin resistance, STAT3 phosphorylation, gluconeogenesis, food intake regulation, energy homeostasis, knockout mice
MeSH terms
Animals, Body Weight, Eating, Energy Metabolism, Gluconeogenesis, Glucose, Glycoproteins, Homeostasis, Hyperphagia, Insulin Resistance, Liver, Mice, Inbred C57BL, Mice, Transgenic, Obesity, Recombinant Proteins, Receptors, Interleukin, Mice, Knockout, Interleukin-18, Intercellular Signaling Peptides and Proteins, STAT3 Transcription Factor, Mice, Receptors, Interleukin-18, Interleukin-18 Receptor alpha Subunit

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