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Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):11097-102. Epub 2007 Jun 19.

Interleukin-18 controls energy homeostasis by suppressing appetite and feed efficiency.

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Harold L. Dorris Neurological Research Institute, Committee on the Neurobiology of Addictive Disorders, and Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, CA 92037, USA.


Circulating levels of the cytokine interleukin 18 (IL-18) are elevated in obesity. Here, we show that administration of IL-18 suppresses appetite, feed efficiency, and weight regain in food-deprived male and female C57BL/6J mice. Intraperitoneal vs. intracerebroventricular routes of IL-18 administration had similar potency and did not promote formation of a conditioned taste aversion (malaise-like behavior). Mice partially (Il18(+/-)) or totally (Il18(-/-)) deficient in IL-18 were hyperphagic by young adulthood, with null mutants then becoming overweight by the fifth month of life. Adult Il18(-/-) mice gained 2- to 3-fold more weight than WT mice per unit energy consumed of low- or high-fat diet. Indirect calorimetry revealed reduced energy expenditure in female Il18(-/-) mice and increased respiratory exchange ratios [volume of carbon dioxide production (VCO(2))/volume of oxygen consumption (VO(2))] in mutants of both sexes. Hyperphagia continued in maturity, with overeating greatest during the mid- to late-dark cycle. Relative white fat-pad mass of Il18(-/-) mice was approximately 2- to 3-fold greater than that of WT, with gonadal, mesenteric, and inguinal depots growing most. The data suggest that endogenous IL-18 signaling modulates food intake, metabolism, and adiposity during adulthood and might be a central or peripheral pharmacological target for controlling energy homeostasis.

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