Divergence in Aerobic Capacity Drives Liver and Brain Health

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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.