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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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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/总结