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 阿尔茨海默病（AD）是最常见的痴呆症形式，引起可怕的个人和经济损失。 大多数AD病例是散发的，没有已知的直接遗传原因。有几个因素与AD密切相关 风险包括两种糖尿病（T2 D）和最近的脂肪肝疾病的代谢疾病状态。物理 特征，有氧能力，在运动中使用氧气的最大能力，已经独立地与 增加T2 D、脂肪肝和AD的风险。内在有氧能力如何独立于日常生活影响疾病 活动或锻炼仍然相对未知。我们使用根据内在有氧能力差异而选择性饲养的大鼠 揭示机制的能力。双向人工选育造就高低容量跑者 (HCR/LCR）大鼠品系的内在有氧能力不同。HCR/LCR大鼠不暴露于运动， 在久坐的情况下，内在有氧能力有40%的差异。LCR非常高 易受高脂饮食（HFD）诱导的肥胖、肝脂肪变性、胰岛素抵抗、神经变性 寿命较短（4-6个月）。相比之下，HCR对HFD诱导的脂肪变性、胰岛素抵抗和胰岛素抵抗具有抗性。 抵抗力和肥胖。这种多基因模型更准确地反映了内在有氧能力的影响 对人类健康和死亡率的影响，更好地代表了对临床发展的保护或易感性， 与其他动物模型相比，许多慢性疾病如T2 D、肝脂肪变性和AD。子公司 格兰特（R 01 DK 121497）研究了内在有氧能力和运动在介导肝硬化风险中的作用。 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HCR/LCR大鼠的大脑样本，发现磷酸化tau蛋白、淀粉样β蛋白 （Aβ）（两者都是AD病理学标志）和线粒体功能改变。HCR/LCR大鼠 不是AD的转基因模型;而是更忠实地代表临床联系的多基因模型 有氧能力、运动和慢性疾病之间的关系。我们建议检查HCR/LCR的大脑 大鼠和久坐/运动的小鼠喂食HFD和母体R 01。我们亦会研究 肝源性排泄物（代谢物、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，全身人体测量学和有氧能力联系起来。的 这里提出的工作是我们正在进行的研究的自然延伸，并将通过建立 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很好- 在NOT-AG-20-034的范围内。