Combined interleukin-6 and interleukin-1 deficiency causes obesity in young mice

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 1L-6 and IL-1Ra (IL-6(-/-) IL-1Ra(-/-)) and IL-6, IL-1 alpha, and IL-1 beta (IL-6(-/-) IL-1(-/-)). IL-6(-/-) IL-1Ra(-/-) mice exhibited a lean phenotype, similar to IL-IRa-'- 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 IL6(-/-) 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 bath involved in the regulation of body fat in a redundant manner in young mice.