Interleukin-18 null mutation increases weight and food intake and reduces energy expenditure and lipid substrate utilization in high-fat diet fed mice

Brain Behav Immun. 2014 Mar;37:45-53. doi: 10.1016/j.bbi.2013.12.001. Epub 2013 Dec 6.


Objective: The proinflammatory cytokine interleukin-18 (IL-18) putatively modulates food intake and energy metabolism, but the effects of IL-18 in high-fat diet fed animals are unknown. Whether IL-18 alters basal metabolic rate or metabolic processes of living is unknown. Here, we tested the hypothesis that IL-18 modulates weight gain, energy intake, whole-body energy expenditure, and utilization of lipid as a fuel substrate in high-fat diet fed mice.

Methods: Food intake, whole-body metabolism, and motor activity of IL-18 knockout mice were compared to those of wildtype littermates; anorectic effects of intracerebroventricular IL-18 administration were compared between IL-18 receptor knockout, IL-18/IL-18R knockout and wildtype mice.

Results: Chow-reared IL-18 knockout mice were overweight at 6 months of age and then gained excess weight on both low-fat and high-fat diets, ate more high-fat diet, and showed reduced whole-body energy expenditure and increased respiratory exchange ratios. Reductions in energy expenditure of IL-18 knockout mice were seen across fasting vs. feeding conditions, low- vs. high-fat diets, high vs. low levels of physical activity and times of day, suggesting actions on basal metabolic rate. The circadian amplitude of energy expenditure, but not respiratory exchange ratio, food intake, or motor activity, also was blunted in IL-18 knockout mice. Central IL-18 administration reduced high-fat diet intake in wildtype mice, but not in mice lacking the IL-18 receptor.

Conclusion: The loss-of-function results support the hypothesis that endogenous IL-18 suppresses appetite and promote energy expenditure and lipid fuel substrate utilization not only during sickness, but also in healthy adults consuming high-fat diets.

Keywords: Body weight; Cosinor analysis or circadian rhythm; Energy expenditure or metabolism; Food intake or appetite; High-fat diet; Indirect calorimetry; Interleukin-18; Locomotor or physical activity; Obesity or overweight; Proinflammatory cytokine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diet, High-Fat
  • Eating
  • Energy Metabolism
  • Female
  • Interleukin-18 / genetics
  • Interleukin-18 / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity / physiology
  • Mutation
  • Receptors, Interleukin-18 / genetics
  • Receptors, Interleukin-18 / physiology*
  • Weight Gain


  • Interleukin-18
  • Receptors, Interleukin-18