Molecular Transducers of Physical Activity: Liver Adaptations Drive Brain Benefits

项目总结/摘要 缺乏身体活动与至少40种慢性疾病有关，包括胰岛素抵抗、2型糖尿病、 非酒精性脂肪肝、晚期脑老化、认知丧失和神经变性。与此相反， 定期锻炼和保持较高的心肺适应性，通过保持每一个 这些因素，并降低风险的无数慢性疾病。虽然锻炼的有益效果是 虽然这些益处得到了广泛的认可，但对支持这些益处的分子机制的了解却较少。 MoTrPAC最近发布的现有文献和数据表明，肝源性因素可能在肝硬化中起核心作用。 在运动的系统效益中的作用。本提案中的研究将描述已知和未知的因素 运动后从肝脏中提取，可以作为运动的分子转换器并驱动积极的适应 肝脏骨骼肌和大脑健康我们专注于MoTrPAC数据，揭示了稳健的约200倍急性 运动诱导孤儿核受体神经源性克隆77肝脏mRNA表达上调 （Nur 77或NR 4A 1）与肝成纤维细胞生长因子21（FGF 21）升高相关 mRNA和血浆酮水平升高。Nur 77和FGF 21密切相关，因为Nur 77在转录水平上与FGF 21的表达相关。 调节FGF 21，并且已知两者都调节肝酮生成。此外，FGF 21和酮体均 主要来源于肝脏，并且已知两者都具有强的全身和神经保护特性。然而，在这方面， 关于这些因素在运动介导的大脑和认知健康变化中的作用知之甚少。这里 我们将检验我们的中心假设，即运动诱导的肝脏适应是分子生物学的核心。 骨骼肌和大脑在急性和慢性运动中发生的适应。我们将机械地 询问肝脏Nur 77（通过肝脏特异性AAV-shRNA敲低方法）是否是运动诱导的关键性 在雄性和雌性Fischer 344大鼠中驱动肝FGF 21和酮产生的因子（目的1）。同样地， 我们将通过敲低肝脏HMG-CoA合酶2（HMGCS 2，关键的调节因子）直接靶向生酮， 肝生酮酶）（目的1）。此外，我们还将对细胞外囊泡进行无偏筛选 以及肝脏对急性和慢性运动训练的反应中释放的miRNAs，并测试是否有 来源于肝脏的新型分泌因子调节神经元和骨骼肌中的碳水化合物和脂质代谢 肌细胞（Aim 2）。总的来说，我们提出的方法将建立关键的机械重要性， Nur 77和HMGCS 2在肝脏、骨骼肌、 和大脑健康。此外，这些研究还可能发现其他新的运动诱导分子， 来自肝脏的换能器。

PROJECT SUMMARY/ABSTRACT Physical inactivity is linked to at least 40 chronic disease conditions including insulin resistance, type 2 diabetes, nonalcoholic fatty liver disease, advanced brain aging, loss of cognition, and neurodegeneration. In contrast, regular exercise and maintenance of higher cardiorespiratory fitness expands health-span by maintaining each of these factors and reducing risk for a myriad of chronic conditions. While the beneficial effects of exercise are extensively recognized, the molecular mechanism(s) underpinning these benefits are less well understood. Existing literature and data recently released by MoTrPAC indicate that liver-derived factors may play a central role in the systemic benefit of exercise. Studies in this proposal will profile known and unknown factors released from the liver after exercise that may serve as molecular transducers of exercise and drive positive adaptations in liver, skeletal muscle, and brain health. We have focused on MoTrPAC data revealing a robust ~200-fold acute exercise induced upregulation in hepatic mRNA expression of orphan nuclear receptor neuro-derived clone 77 (Nur77 or NR4A1) that occurred in conjunction with an elevation in hepatic fibroblast growth factor 21 (FGF21) mRNA and elevated plasma ketone levels. Nur77 and FGF21 are intimately linked, as Nur77 transcriptionally regulates FGF21 and both are known to regulate hepatic ketogenesis. In addition, both FGF21 and ketone bodies are primarily liver-derived and both are known to have strong systemic and neuroprotective properties. However, little is known about the role of these factors in exercise-mediated changes in brain and cognitive health. Here we will test our central hypothesis that exercise-induced hepatic adaptations are central to the molecular adaptations that occur in the skeletal muscle and brain with acute and chronic exercise. We will mechanistically interrogate if hepatic Nur77 (via a liver-specific AAV-shRNA knockdown approach) is a critical exercise-induced factor driving both hepatic FGF21 and ketone production in male and female Fischer 344 rats (Aim 1). Similarly, we will target ketogenesis directly by knocking down liver HMG-CoA synthase 2 (HMGCS2, the key regulatory enzyme in hepatic ketogenesis) (Aim 1). In addition, we will perform an unbiased screen of extracellular vesicles and miRNAs released by the liver in response to acute and chronic exercise training and test whether there are novel secreted factors originating in the liver regulate carbohydrate and lipid metabolism in neuronal and skeletal muscle cells (Aim 2). Collectively, our proposed approaches will establish the critical mechanistic importance of Nur77 and HMGCS2 in the regulation of hepatic FGF21 and ketone-mediated benefits in liver, skeletal muscle, and brain health. In addition, these studies will also potentially identify other novel exercise-induced molecular transducers originating from the liver.