Combined Interleukin-6 and Interleukin-1 Deficiency Causes Obesity in Young Mice

Abstract

Proinflammatory cytokines including interleukin (IL)-1 and IL-6 exert pleiotropic effects on the neuro-immuno-endocrine system. Previously, we showed that IL-1 receptor antagonist–deficient (IL-1Ra^−/−) mice show a lean phenotype due to an abnormal lipid metabolism. On the contrary, it was reported that IL-6^−/− mice exhibit obesity after 6 months of age. This study sought to assess the roles of IL-1 and IL-6 in body weight homeostasis. We generated mice deficient in IL-6 and IL-1Ra (IL-6^−/− IL-1Ra^−/−) and IL-6, IL-1α, and IL-1β (IL-6^−/− IL-1^−/−). IL-6^−/− IL-1Ra^−/− mice exhibited a lean phenotype, similar to IL-1Ra^−/− mice. On the other hand, IL-6^−/− IL-1^−/− mice became obese as early as 10 weeks of age, while IL-1^−/− mice and IL-6^−/− mice were normal at this age. The daily food intake was significantly higher in IL-6^−/− IL-1^−/− mice than in IL-6^−/− IL-1^+/− mice, while energy expenditure was comparable in these two strains. Acute anorexia induced by peripheral administration of IL-1 was significantly suppressed in IL-6^−/− IL-1^−/− mice, but not in IL-1^−/− mice or IL-6^−/− mice compared with wild-type mice. These results indicate that IL-1 and IL-6 are both involved in the regulation of body fat in a redundant manner in young mice.