Divergence in Aerobic Capacity Drives Liver and Brain Health

有氧能力的差异促进肝脏和大脑健康

• 批准号: 10286535
• 负责人: John P Thyfault
• 金额: $ 37.76万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10286535
• 关键词: Acute; Aerobic; Age; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Animal Model; Astrocytes; Bile Acid Biosynthesis Pathway; Bile Acids; Brain; Breeding; Cell physiology; Chronic; Chronic Disease; Clinical; Cognition; Data; Dementia; Diabetes Mellitus; Disease; Elderly; Epigenetic Process; Excretory function; Exercise; Exposure to; Fatty Liver; Generations; Genes; Genetic; Health; Health Care Costs; Healthcare Systems; High Fat Diet; Hormones; Human; Individual; Insulin Resistance; Link; Lipids; Liver; Liver Mitochondria; Liver diseases; Longevity; Mediating; Metabolic Diseases; Mitochondria; Modeling; Mus; Nerve Degeneration; Neuroglia; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Oxygen; Parents; Pathologic; Pathway interactions; Pattern; Phagocytes; Phenotype; Predisposition; Proteins; Proteomics; Rat Strains; Rattus; Reporting; Research; Resistance; Risk; Running; Sampling; Serum; Spectrophotometry; Synapses; Work; bile acid metabolism; bile duct; brain health; cardiorespiratory fitness; clinical development; cytokine; diet-induced obesity; disorder risk; exercise intensity; experimental study; liver function; liver injury; middle age; mortality; nonalcoholic steatohepatitis; novel; parent grant; proteostasis; resilience; sedentary; tau Proteins; tau-1; trait; western diet

Project Abstract/Summary Alzheimer’s Disease (AD) is the most common form of dementia evoking a terrible personal and financial toll. Most AD cases are sporadic with no known direct genetic cause. Several factors associate strongly with AD risk including metabolic disease states of two diabetes (T2D) and more recently fatty liver disease. A physical trait, aerobic capacity, the maximal capacity to use oxygen during exercise, has been independently linked to increased risk for T2D, fatty liver, and AD. How intrinsic aerobic capacity impacts disease independent of daily activity or exercise remains relatively unknown. We use rats selectively bred for divergence in intrinsic aerobic capacity to reveal mechanisms. Two-way artificial selective breeding created high and low capacity runner (HCR/LCR) rat strains divergent for intrinsic aerobic capacity. HCR/LCR rats are not exposed to exercise and display a contrasting, 40% difference in intrinsic aerobic capacity in a sedentary condition. LCR are highly susceptible to high fat diet (HFD)-induced obesity, hepatic steatosis, insulin resistance, neurodegeneration, and a shorter lifespan (4-6 months). In contrast, the HCR are resistant to HFD induced steatosis, insulin resistance and obesity. This polygenetic model more accurately reflects the impact of intrinsic aerobic capacity on human health and mortality, and better represents the protection or susceptibility for clinical development of many chronic diseases such as T2D, hepatic steatosis, and AD compared to other animal models. Our parent grant (R01DK121497) investigates intrinsic aerobic capacity and exercise in mediating the risk of hepatic steatosis through liver mitochondrial function/bile acid synthesis and epigenetic/proteomic modulations. We recently examined brain samples from HCR/LCR rats and found increased phosphorylated tau, amyloid beta (Aβ) (both are AD pathological hallmarks) and altered mitochondrial function. Importantly, HCR/LCR rats are not transgenic models of AD; but a polygenetic model which more faithfully represents the clinical links between aerobic capacity, exercise, and chronic disease. We propose to examine the brains from HCR/LCR rats and sedentary/exercised mice fed a HFD in conjunction with the parent R01. We will also examine the effects of liver derived excretions (metabolites, hormones, proteins) on neuronal and glial cell health and function. We will have the ability to correlate liver health, systemic anthropometrics, and aerobic capacity. The work proposed here is a natural extension of our ongoing research and will further the AD field by establishing mechanistic links between aerobic capacity, liver health, and AD. The experiments we now propose are well- within the scope of NOT-AG-20-034.

项目摘要/摘要 阿尔茨海默氏病（AD）是痴呆症最常见的形式，引起了个人和经济损失。 大多数AD病例都是零星的，没有已知的直接遗传原因。与AD密切相关的几个因素 风险包括两种糖尿病（T2D）和最近脂肪肝病的代谢疾病状态。身体 特质，有氧能力，运动过程中使用氧气的最大能力已与 T2D，脂肪肝和AD的风险增加。固有的有氧运动能力如何影响疾病独立于每日 活动或运动仍然相对未知。我们使用大鼠有选择性地育出固有有氧运动的分歧 揭示机制的能力。双向人造选择性繁殖创造了高容量和低容量跑步者 （HCR/LCR）大鼠菌株的固有有氧能力发散。 HCR/LCR大鼠不暴露于运动和 在久坐的条件下显示出对比度，内在有氧运动能力的差异为40％。 LCR高度 容易受到高脂肪饮食（HFD）诱导的肥胖症，肝脂肪变性，胰岛素抵抗，神经变性， 寿命较短（4-6个月）。相反，HCR对HFD诱导的脂肪变性具有抗性 抵抗和肥胖。这种多基因模型更准确地反映了内在有氧能力的影响 关于人类的健康和死亡率，更好地代表了临床发展的保护或易感性 与其他动物模型相比，许多慢性疾病，例如T2D，肝脂肪变性和AD。我们的父母 Grant（R01DK121497）研究了内在的有氧能力和锻炼，以介导肝风险 通过肝线粒体功能/胆汁酸合成和表观遗传/蛋白质组学调节的脂肪变性。我们 最近检查了来自HCR/LCR大鼠的脑样品，发现磷酸化的TAU淀粉样蛋白β增加 （Aβ）（两者都是AD病理标志）和线粒体功能的改变。重要的是，HCR/LCR大鼠是 不是AD的转基因模型；但是一个更忠实地代表临床联系的多基因模型 在有氧运动能力，运动和慢性病之间。我们建议检查HCR/LCR的大脑 大鼠和久坐/锻炼的小鼠与父母R01结合使用了HFD。我们还将检查 肝脏衍生泄出（代谢产物，激素，蛋白质）对神经元和神经胶质细胞健康的影响 功能。我们将有能力将肝脏健康，全身性人为测量和有氧能力相关联。这 这里提出的工作是我们正在进行的研究的自然延伸，将通过建立广告领域的进一步发展 有氧能力，肝脏健康和AD之间的机械联系。我们现在提出的实验是很好的 在NOT-AG-20-034的范围内。