Аннотация:Inflammatory conditions are accompanied by profound adaptations of both cellular and systemic metabolism. However, despite extensive investigation of the immune cell metabolism, less is known about the mechanisms of physiological metabolic shifts in the context of inflammation.We employed mouse model of LPS-induced systemic inflammation that results in drastic reprogramming of metabolic state of the organism and demonstrated the key role of IL-6 in regulation of this adaptation. Genetic or pharmacological inactivation of IL-6 significantly abrogated inflammatory effect on glucose homeostasis. In particularly, we have shown that IL-6 regulates gene expression of key enzymes in the glycogen metabolism pathway in the liver of mice during inflammation. This resulted in significant hypoglycaemia and hypothermia in response to inflammatory conditions, that were not evident if IL-6 was inactivated. The involvement of glycogen metabolism pathway in regulation of glucose homeostasis during inflammation was further confirmed by pharmacological inhibition of glycogen phosphorylase. Finally, we found that IL-6 knock-out mice failed to induce fatigue upon LPS challenge as evidenced by RotaRod training. Fatigue, along with other well-described symptoms of so called “sickness behaviour”, could potentially contribute to the energy balance shift towards immune response rather than physical activity. We thus believe that via regulation of systemic metabolism IL-6 launches crucial physiological adaptations to the inflammatory conditions. Altogether our data demonstrate specific role of IL-6 in regulation of systemic metabolism and physiology in the context of inflammation. Further investigation of the mechanisms of these adaptations could potentially lead to the development of new therapies for infection- and cancer-induced multi-organ pathologies such as cachexia.