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Tolerance represents an important part of adaptation to infection. Proinflammatory cytokines, such as IL‐6, IL‐1β, and TNF, are believed to take part in this process, driving the so‐ called “sickness behavior”, but their relative contributions are not yet clarified. Recently, IL‐6 was characterized as the exercise‐ and stress‐induced factor that is regulating systemic metabolism, specifically, the blood glucose level. However, its role in physiological and metabolic adaptations in the context of inflammation remains elusive. In this study we aimed to investigate the contribution of IL‐6 to “sickness metabolism state” that is characterized by the altered blood metabolome and reduced body physical endurance in the context of inflammation. We observed a drastic reduction in RotaRod exercise capacity of WT, but not IL‐6 KO mice, following LPS challenge. Intriguingly, conditional inactivation of IL‐6 in myeloid cells did not affect systemic IL‐6 production and body endurance, while skeletal muscles were identified as the major source of inflammation‐induced IL‐6. Furthermore, inactivation of IL‐6 resulted in elevated glucose and reduced triglycerides levels in the blood in response to LPS as compared to WT mice. Transcriptome analysis revealed deregulated glycogen synthesis and degradation pathways in the liver, as well as lipolysis pathway in white adipose tissue in LPS‐challenged IL‐6 KO as compared to WT mice. Altogether, we propose that physiological and metabolic adaptations to inflammatory conditions constitute a significant part of IL‐6 functions, and they could be employed in the control of the adverse effects of infections, such as sepsis and cytokine storm.