Harnessing Fasting Metabolism to Improve Survival in Bacterial Sepsis

项目总结 传统上，急性疾病的厌食症被认为是面对假定的 高度分解代谢状态。令人惊讶的是，我们发现厌食症对细菌性败血症有保护作用。葡萄糖 在细菌败血症引起的厌食期补充营养是有害的，并会增加死亡率， 即使在没有活体病原体的情况下，如脂多糖(LPS)脓毒症的小鼠模型中也是如此。核心禁食 内毒素脓毒症中激活的代谢途径，包括游离脂肪酸的释放、酮的生成和产生 成纤维细胞生长因子-21(FGF21)，一种介导适应性反应的内分泌成纤维细胞生长因子激素 补充葡萄糖可以抑制饥饿等新陈代谢压力。基因敲除的小鼠 缺乏FGF21或过氧化物酶体增殖物激活受体α，不能产生FGF21或 酮，更容易受到细菌败血症的影响。我们还发现，与正常的禁食反应类似， 细菌败血症时，肝脏和肾脏中会积聚脂滴。新出现的证据表明，脂质 事实上，液滴可能反映了对细胞应激的保护机制，而不是脂毒性。基于我们的 初步数据，我们假设禁食代谢的组成部分是完整的保护机制 支持细菌败血症期间的生存和组织保护。未来五年，Huen的主要目标是 实验室将确定禁食代谢的成分是否和如何：1)FGF21，2)酮体生成，以及 3)脂滴形成，对细菌败血症有保护作用。建议的研究包括使用药理学 这些代谢过程中的关键成分的组织特异性缺失的靶向和遗传小鼠模型。 将使用跨学科的方法来研究先天免疫之间的相互作用的生理学 系统和代谢器官，以阐明多个器官系统之间的复杂相互作用 包括大脑、肝脏、肾脏和心脏，作为对细菌败血症的适应性反应的一部分。最重要的是 我们建议的研究目标是区分病理性代谢途径和保护性代谢途径。 细菌性败血症，询问支持生存的禁食代谢的有益方面，并阐明 行动机制。

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.