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：
10661829
负责人：
Stanislaw Marek Deja
金额：
$ 10.34万
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/10661829
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 Intervention Ketones Knockout Mice 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 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.

项目摘要肥胖症及其并发症的患病率，包括糖尿病和非酒精性脂肪肝病（NAFLD）是重大的医疗危机。这些并发症通过失调而影响肝脏代谢糖异生，脂质合成，线粒体功能和脂肪氧化。 NAFLD通过生活方式改善了干预措施。具有讽刺意味的是，体育活动，运动和有氧能力类似地影响许多此类途径但肝脏脂肪非常低，独立于体重减轻。因此，有氧运动通常是规定的 NAFLD的治疗。肥胖或运动影响肝脏代谢调节的一条途径可能是通过交感神经系统信号。这个5年研究职业的总体目标发展计划是为了促进我从技术专注的研究人员到完全独立的过渡学术科学家研究了体内疾病生理学。这将通过培训来完成生理学，神经生理学和运动的学科，这些学科将用于识别机制肝交感神经信号传导在肥胖和干预过程中控制肝脏代谢通量。高架认为基本的交感信号传导通过α1b肾上腺素受体（AR）发生，这是高度的在小鼠肝脏中表达（包括肝细胞），并已建议刺激肝葡萄糖产生，糖原，糖化，三核酸（TCA）循环和生酮发生的分解。这项目侧重于了解肝α1B-AR如何促进肝粘膜生成失调和肥胖和NAFLD期间的脂肪氧化（AIM 1），以及肝α1B-AR介导有益作用的程度急性（AIM 2）或慢性运动（AIM 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。调查结果会促进我们对肥胖并发症如何改变新陈代谢的知识并提供一种新颖的训练收件人的平台。