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

• 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
• 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

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） 是一场重大的医疗保健危机。这些并发症通过失调影响肝脏代谢 糖异生、脂质合成、线粒体功能和脂肪氧化。 NAFLD 通过生活方式得到改善 干预措施。讽刺的是，体力活动、锻炼和有氧能力同样会影响许多这些途径， 但会显着降低肝脏脂肪，与体重减轻无关。因此，人们普遍认为有氧运动 NAFLD 的治疗。肥胖或运动影响肝脏代谢调节的一种途径可能是 通过交感神经系统发出信号。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识别机制 肝脏交感神经信号在肥胖和干预期间控制肝脏代谢通量。高架 基础交感神经信号传导被认为是通过 α1b 肾上腺素能受体 (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。这 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 急性（目标 2）或慢性运动（目标 3）作为 NAFLD 的治疗方法。使用靶向代谢组学和稳定 同位素输注，我将定量评估 AR 信号如何调节肝脏代谢。研究结果将 增进我们对肥胖并发症如何改变新陈代谢的了解，并提供新颖的培训 为接收者提供平台。