Harnessing Fasting Metabolism to Improve Survival in Bacterial Sepsis

利用禁食代谢来提高细菌性脓毒症的存活率

• 批准号: 10238121
• 负责人: sarah huen
• 金额: $ 41万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10238121
• 关键词: Acute; Anorexia; Brain; Cellular Stress; Complex; Critical Illness; Data; Endocrine; Fasting; Fibroblast Growth Factor; Genetic; Glucose; Goals; Heart; Hormones; Inflammation; Innate Immune System; Ketones; Kidney; Knockout Mice; Laboratories; Lipids; Lipopolysaccharides; Liver; Mediating; Metabolic; Metabolic Pathway; Metabolic stress; Metabolism; Methods; Nonesterified Fatty Acids; Nutritional; Nutritional Support; Organ; PPAR alpha; Pathologic; Patients; Pharmacology; Physiology; Production; Sepsis; Starvation; Supplementation; Tissue Model; Tissues; base; body system; fibroblast growth factor 21; improved; insight; ketogenesis; mortality; mouse model; pathogen; response; septic patients

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.

项目概要 传统上，急性疾病引起的厌食症被认为是面对假定的适应不良反应。 高分解代谢状态。令人惊讶的是，我们发现厌食症对细菌性败血症具有保护作用。葡萄糖 在细菌性败血症引起的厌食期间补充补充剂是有害的并会增加死亡率， 即使在没有活病原体的情况下，如脂多糖（LPS）脓毒症小鼠模型。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、生酮作用和生产 成纤维细胞生长因子 21 (FGF21) 是一种内分泌 FGF 激素，可介导适应性反应 补充葡萄糖可以抑制饥饿等代谢应激。敲除小鼠是 FGF21 或过氧化物酶体增殖物激活受体 α 缺陷，无法产生 FGF21 或 酮，更容易患细菌性败血症。我们还发现，与正常的禁食反应类似， 细菌性败血症期间，脂滴在肝脏和肾脏中积聚。新出现的证据表明，脂质 事实上，液滴可能反映了针对细胞应激而不是脂毒性的保护机制。基于我们的 根据初步数据，我们假设空腹代谢的组成部分是不可或缺的保护机制 支持细菌性败血症期间的生存和组织保护。未来五年，胡恩的主要目标 实验室将确定空腹代谢是否以及如何进行：1) FGF21，2) 生酮作用，以及 3) 脂滴形成，对细菌性败血症具有保护作用。拟议的研究包括使用药理学 组织特异性删除这些代谢过程关键成分的靶向和遗传小鼠模型。 将使用跨学科方法来研究先天免疫之间的相互作用生理学 系统和代谢器官，以阐明多个器官系统之间复杂的相互作用 包括大脑、肝脏、肾脏和心脏，作为对细菌性败血症适应性反应的一部分。首要的 我们提出的研究的目的旨在区分病理性和保护性代谢途径 细菌性败血症，探讨支持生存的禁食代谢的有益方面，并阐明 行动机制。