Molecular Transducers of Physical Activity: Liver Adaptations Drive Brain Benefits

项目摘要/摘要 缺乏运动与至少40种慢性疾病有关，包括胰岛素抵抗、2型糖尿病、 非酒精性脂肪性肝病、高级脑老化、认知丧失和神经退化。相比之下， 定期锻炼和保持较高的心肺健康水平通过保持各自的健康水平来扩大健康跨度 减少这些因素的风险，降低患各种慢性病的风险。虽然锻炼的好处是 虽然得到了广泛的认可，但支撑这些益处的分子机制(S)却知之甚少。 MoTrPAC最近发布的现有文献和数据表明，肝源性因子可能在 在运动的全身性益处中的作用。这项提案中的研究将概述已发布的已知和未知因素 从运动后的肝脏中释放出来的，可能作为运动的分子传导器，驱动正向适应 在肝脏、骨骼肌和大脑健康方面。我们关注的是MoTrPAC数据，该数据显示 运动诱导孤儿核受体神经源性克隆77肝脏mRNA表达上调 (Nur77或NR4A1)与肝成纤维细胞生长因子21(FGF21)的升高同时发生 信使核糖核酸和血酮水平升高。Nur77和FGF21紧密相连，因为Nur77在转录上 调节FGF21，已知两者都调节肝酮的生成。此外，FGF21和酮体 主要来自肝脏，已知两者都具有很强的全身和神经保护特性。然而， 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，人们知之甚少。这里 我们将验证我们的中心假设，即运动诱导的肝脏适应是分子的中心。 骨骼肌和大脑在急性和慢性运动中发生的适应。我们会机械地 询问肝脏Nur77(通过肝脏特异性AAV-shRNA敲除方法)是否是运动诱导的关键 驱动雄性和雌性Fischer 344大鼠肝脏FGF21和酮产生的因素(目标1)。同样， 我们将通过敲除肝脏HMG-CoA合成酶2(HMGCS2，关键调控因子)来直接靶向酮的生成 肝酮生成中的酶)(目标1)。此外，我们将对细胞外小泡进行无偏筛选 以及肝脏在急性和慢性运动训练中释放的miRNAs，并测试是否有 源于肝脏的新的分泌因子调节神经元和骨骼的碳水化合物和脂肪代谢 肌肉细胞(目标2)。总的来说，我们提出的方法将确立关键的机械重要性 Nur77和HMGCS2在调节肝脏FGF21和酮介导的肝脏、骨骼肌、 和大脑健康。此外，这些研究还可能确定其他新的运动诱导分子 来自肝脏的传感器。

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.