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Molecular Transducers of Physical Activity: Liver Adaptations Drive Brain Benefits

身体活动的分子传感器：肝脏适应推动大脑获益

基本信息

批准号：
10264908
负责人：
FRANK W BOOTH
金额：
$ 51.61万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10264908
关键词：
3-hydroxy-3-methylglutaryl-coenzyme A Acute Aging Attention Automobile Driving Brain Cell Line Chronic Chronic Disease Citric Acid Cycle Clinical Cognition Cognitive Data Enzymes Exercise Exercise Test Extrahepatic Exudate Female Genetic Transcription Glucose Health Hepatic Inbred F344 Rats Insulin Resistance Ketone Bodies Ketones Link Literature Liver Liver Mitochondria Location Maintenance Mediating Mediator of activation protein Memory Messenger RNA Metabolic Metabolic Diseases Metabolism MicroRNAs Mitochondria Molecular Muscle Muscle Fibers NR4A1 gene Nerve Degeneration Neurocognitive Neurons Non-Insulin-Dependent Diabetes Mellitus Nuclear Orphan Receptor Obesity Organ Performance Peripheral Physical activity Plasma Play Production Property Rattus Reaction Regulation Respiration Risk Role Sampling Skeletal Muscle Slice Testing Tissues Transducers Up-Regulation aging brain brain health brain metabolism carbohydrate metabolism cardiorespiratory fitness exercise training extracellular vesicles fibroblast growth factor 21 glucose metabolism healthspan hepatic vein improved ketogenesis ketogentic knock-down lipid metabolism liver metabolism mRNA Expression male mitochondrial metabolism neurogenesis non-alcoholic fatty liver disease novel physical inactivity relating to nervous system release factor response sedentary skeletal muscle metabolism small hairpin RNA white matter

项目摘要

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.

项目总结/文摘