With a yearly burden of 49 million cases and 11 million deaths, sepsis is considered as the major unmet medical need of today. The current treatments are rather supportive than curative and mainly consist of antibiotics and organ support. Our research proves that sepsis is associated with a failing ‘starvation response’ whereby the septic mammal acutely generates energy rich metabolites such as lactate, but fails to convert them, in the liver, in useful molecules, because in this organ the transcription factor Glucocorticoid receptor (GR) becomes completely inactive. Interestingly, our data show that injection of lactate is never toxic, but when the GR is compromised this lactate induces an acute lethal response via an uncontrolled VEGF production. This lactate-induced lethal shock was also observed in mice lacking adrenals (ADX mice) but was, in such mice, prevented by dexamethasone, a synthetic glucocorticoid (GC), pretreatment. Hence, I want to investigate the source and mechanisms responsible for increased lactate production in sepsis and elucidate how lactate induces a fast and lethal response via VEGF production. Finally, since our data showed that lactate can induce GC production, and in this way circumvent its own toxicity, we will study the mechanisms of a potential lactate-mediated HPA-axis activation.