Sympathetic Control of Liver Metabolism in Exercise and Obesity

运动和肥胖中肝脏代谢的交感神经控制

基本信息

批准号：
10506749
负责人：
Stanislaw Marek Deja
金额：
$ 10.49万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-07 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10506749
关键词：
Acute Adrenergic Receptor Aerobic Aerobic Exercise Affect Amino Acids Body Weight decreased Cell Respiration Chronic Citric Acid Cycle Complication Development Plans Diabetes Mellitus Discipline Disease Event Exercise Exhibits Fatty Liver Fatty acid glycerol esters Functional disorder Genetic Gluconeogenesis Glucose Glycogen Goals Healthcare Hepatic Hepatocyte High Fat Diet Human Impairment Infusion procedures Insulin Ketones Knock-out Knowledge Lipids Liver Mediating Metabolic Metabolic Control Metabolism Mitochondria Monitor Mus Neurons Norepinephrine Obese Mice Obesity Output Pathway interactions Physical activity Physiology Play Prevalence Process Production Protocols documentation Receptor Signaling Regulation Research Research Personnel Role Route Running Scientist Signal Transduction Skeletal Muscle Stimulus Stress Sympathetic Nervous System Testing Tissues Tracer Training Training Programs Triglycerides career development cost exercise capacity fighting glucose production hepatic gluconeogenesis improved in vivo ketogenesis ketogentic lifestyle intervention lipid metabolism liver function liver metabolism metabolomics neurophysiology non-alcoholic fatty liver disease novel obesity treatment oxidation receptor binding receptor function remediation response stable isotope tool treadmill

项目摘要

PROJECT SUMMARY The prevalence of obesity and its complications, including diabetes and non-alcoholic fatty liver disease (NAFLD) are a significant health care crisis. These complication impact liver metabolism by dysregulating gluconeogenesis, lipid synthesis, mitochondrial function, and fat oxidation. NAFLD is improved by lifestyle interventions. Ironically, physical activity, exercise, and aerobic capacity affect many of these pathways similarly, but profoundly lower liver fat independent of weight loss. Hence, aerobic exercise is commonly prescribed therapy for NAFLD. One route by which obesity or exercise influence regulation of liver metabolism may be by signals through the sympathetic nervous system. The overarching goal of this 5-year research career development plan is to facilitate my transition from a technically focused researcher to a fully independent academic scientist investigating the in vivo physiology of disease. This will be accomplished by training in disciplines of physiology, neurophysiology, and exercise that will be used to identify mechanisms by which hepatic sympathetic nervous signaling controls liver metabolic flux during obesity and interventions. Elevated basal sympathetic signaling is thought to occur through the α1b adrenergic receptor (AR), which is highly expressed in mouse liver (including hepatocytes) and has been suggested to stimulate hepatic glucose production, breakdown of glycogen, gluconeogenesis, tricarboxylic acid (TCA) cycle and ketogenesis. This project focuses on understanding how hepatic α1b-AR contributes to dysregulated hepatic gluconeogenesis and fat oxidation during obesity and NAFLD (Aim 1), and the degree to which liver α1b-AR mediates beneficial effects of acute (Aim 2) or chronic exercise (Aim 3) as treatments of NAFLD. Using targeted metabolomics and stable isotope infusions, I will quantitatively evaluate how AR signaling regulates liver metabolism. The findings will advance our knowledge of how metabolism is altered by complications of obesity and provide a novel training platform for the recipient.

项目概要肥胖及其并发症的患病率，包括糖尿病和非酒精性脂肪肝（NAFLD）这些并发症通过失调影响肝脏代谢。生活方式可改善糖异生、脂质合成、线粒体功能和脂肪氧化。具有讽刺意味的是，体力活动、锻炼和有氧能力对许多这些途径的影响类似，但与减肥无关，可显着降低肝脏脂肪，因此，通常会进行有氧运动。 NAFLD 的治疗方法之一是肥胖或运动影响肝脏代谢调节。通过交感神经系统发出信号是这五年研究生涯的总体目标。发展计划是为了促进我从专注于技术的研究人员转变为完全独立的研究人员研究疾病体内生理学的学术科学家这将通过培训来完成。生理学、神经生理学和运动学科将用于确定机制肝脏交感神经信号在肥胖和干预期间控制肝脏代谢通量。交感神经信号传导被认为是通过 α1b 肾上腺素能基础受体 (AR) 发生的，该受体高度在小鼠肝脏（包括肝细胞）中表达，并被认为可以刺激肝葡萄糖糖原的产生、分解、糖异生、三羧酸（TCA）循环和酮生成。该项目的重点是了解肝脏 α1b-AR 如何导致肝脏糖异生失调和肥胖和 NAFLD 期间的脂肪氧化（目标 1），以及肝脏 α1b-AR 介导有益作用的程度使用靶向代谢组学和稳定疗法治疗急性（目标 2）或慢性运动（目标 3）。同位素输注，我将定量评估 AR 信号如何调节肝脏代谢。我们了解肥胖并发症如何促进新陈代谢，并提供新颖的培训为接收者提供平台。