Harnessing Fasting Metabolism to Improve Survival in Bacterial Sepsis

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PROJECT SUMMARY Anorexia of acute illness has traditionally been considered a maladaptive response in the face of a presumed hyper-catabolic state. Surprisingly, we found that anorexia is protective in bacterial sepsis. Glucose supplementation during the period of anorexia induced by bacterial sepsis is detrimental and promotes mortality, even in the absence of live pathogen as in the mouse model of lipopolysaccharide (LPS) sepsis. Core fasting metabolic pathways activated in LPS sepsis, including liberation of free fatty acids, ketogenesis, and production of fibroblast growth factor-21 (FGF21), an endocrine FGF hormone that mediates adaptive responses to metabolic stresses such as starvation, are suppressed by glucose supplementation. Knockout mice that are deficient in FGF21 or in peroxisome proliferator-activated receptor alpha, which cannot produce FGF21 or ketones, are more susceptible to bacterial sepsis. We have also found that similar to normal fasting responses, lipid droplets accumulate in the liver and kidney during bacterial sepsis. Emerging evidence suggests that lipid droplets may in fact reflect protective mechanisms against cellular stress rather than lipotoxicity. Based on our preliminary data, we hypothesize that components of fasting metabolism are integral protective mechanisms that support survival and tissue protection during bacterial sepsis. Over the next five years, key goals for the Huen laboratory are to determine whether and how components of fasting metabolism: 1) FGF21, 2) ketogenesis, and 3) lipid droplet formation, are protective in bacterial sepsis. Proposed studies include using pharmacologic targeting and genetic mouse models of tissue-specific deletion of key components of these metabolic processes. Interdisciplinary methods will be used to investigate the interactive physiology between the innate immune system and metabolic organs, in order to elucidate the complex interactions between multiple organ systems including the brain, liver, kidney and heart as part of the adaptive response to bacterial sepsis. The overarching objectives of our proposed studies aim to differentiate between pathologic and protective metabolic pathways in bacterial sepsis, interrogate the beneficial aspects of fasting metabolism that support survival, and elucidate the mechanisms of action.