Harnessing Fasting Metabolism to Improve Survival in Bacterial Sepsis

项目摘要 传统上，急性疾病的厌食症被认为是面对假定的疾病时的适应不良反应。 高分解代谢状态令人惊讶的是，我们发现厌食症在细菌性败血症中具有保护作用。葡萄糖 在由细菌性脓毒症引起的厌食期间的补充是有害的并促进死亡率， 即使在没有活病原体的情况下，如在脂多糖（LPS）脓毒症的小鼠模型中。核心禁食 LPS脓毒症中激活的代谢途径，包括游离脂肪酸的释放、酮生成和 成纤维细胞生长因子-21（FGF 21），一种内分泌FGF激素， 通过补充葡萄糖来抑制代谢应激如饥饿。敲除小鼠 缺乏FGF 21或过氧化物酶体增殖物激活受体α，不能产生FGF 21或 酮更容易感染细菌性败血症。我们还发现，与正常的禁食反应类似， 脂滴在细菌性脓毒症期间在肝脏和肾脏中积累。新出现的证据表明， 液滴实际上可能反映了对抗细胞应激的保护机制，而不是脂毒性。基于我们 根据初步数据，我们假设禁食代谢的组成部分是不可或缺的保护机制， 支持细菌败血症期间的存活和组织保护。在未来五年内，Huen的主要目标 实验室正在确定空腹代谢的组成部分是否以及如何：1）FGF 21，2）生酮， 3)脂滴形成在细菌性脓毒症中具有保护作用。拟议的研究包括使用药理学 这些代谢过程的关键成分的组织特异性缺失的靶向和遗传小鼠模型。 跨学科的方法将被用来调查之间的相互作用生理先天免疫 系统和代谢器官，以阐明多器官系统之间的复杂相互作用 包括脑、肝、肾和心脏作为对细菌性脓毒症的适应性反应的一部分。总体 我们提出的研究目的是区分病理性和保护性代谢途径， 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.