In vivo hepato-renal metabolic flux dysregulation in obesity

肥胖体内肝肾代谢通量失调

• 批准号: 10644303
• 负责人: Clinton Michael Hasenour
• 金额: $ 12.06万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10644303
• 关键词: Acceleration; Adult; Biological Models; Cell Respiration; Chronic; Chronic Kidney Failure; Citric Acid Cycle; Continuity of Patient Care; Coupled; Data; Development; Development Plans; Diabetes Mellitus; Diabetic Nephropathy; Dietary Intervention; Disease; Disease Progression; Ensure; Etiology; Exhibits; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Foundations; Genetic; Gluconeogenesis; Glucose; Goals; Health; Hepatic; Human; Hypoglycemia; Impairment; Inflammation; Intervention; Kidney; Knock-out; Knowledge; Link; Lipids; Liver; Mediating; Mentors; Metabolic; Metabolic Control; Metabolic Diseases; Metabolic dysfunction; Metabolism; Methods; Mitochondria; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Overnutrition; Oxidative Stress; Pathogenicity; Pathway interactions; Patient Care; Patients; Predisposition; Prevalence; Proximal Kidney Tubules; Publishing; Regulation; Research; Research Infrastructure; Role; Steatohepatitis; Stress; Techniques; Testing; Therapeutic Intervention; Time; Tissues; Training; Transgenic Mice; Universities; Work; burden of illness; career; career development; clinically relevant; counterregulation; dietary; euglycemia; glucose metabolism; glucose production; glycemic control; improved; in vivo; inhibitor; innovation; insight; kidney metabolism; lens; liver injury; liver metabolism; member; metabolic abnormality assessment; mitochondrial dysfunction; mitochondrial metabolism; new technology; non-alcoholic fatty liver disease; novel; novel therapeutics; obesity development; oxidation; personalized care; preservation; stable isotope; therapeutic target; tissue injury; western diet

Project Summary The liver and kidney are the major organs where glucose biosynthesis is coupled to mitochondrial metabolism. Previous studies demonstrate that overnutrition accelerates whole-body gluconeogenesis (GNG) and citric acid cycle (CAC) activity in vivo. A limitation of prior research is that the unique contributions of the liver and kidney to whole-body GNG and CAC fluxes have been difficult to disentangle in vivo. The inability to discern hepatic from renal metabolic fluxes represents a significant gap in knowledge, as obesity may not only cause an ectopic accumulation of lipid but also an “ectopic redistribution” of gluconeogenic function that disproportionately stresses the kidney. We hypothesize that renal GNG and CAC activity are disproportionately elevated in obesity, which contributes to the dysregulation of whole-body glucose metabolism and promotes mitochondrial dysfunction and oxidative tissue damage in the kidney. The scientific aims of this proposal are to (i) determine whether the progressive development of obesity disproportionately impacts renal gluconeogenic and oxidative metabolism, (ii) assess whether gluconeogenic overload on the kidney accelerates oxidative metabolism and stress during obesity, and (iii) identify metabolic mechanism(s) by which SGLT2 inhibitor treatment reduces hepato-renal lipotoxicity in vivo. The aims of our project will be accomplished using a novel, metabolic flux modeling system that simultaneously determines gluconeogenic and oxidative metabolic fluxes in the liver and kidney in vivo. This work is innovative because it examines the etiology and treatment of metabolic disease through the lens of multi-organ fluxomics while focusing on an understudied aspect of gluco(dys)regulation. It is significant because it will identify organ-specific metabolic nodes that may be better targeted to improve glycemic control and reduce damage in the kidney and liver. Results from this K01 project, the unique expertise of each member of my mentoring committee, and the diabetes research infrastructure at Vanderbilt University will be leveraged to achieve my career objective of an independent career studying metabolic regulation in diabetic kidney disease and hypoglycemic counter-regulation. As such, this project integrates a career development plan with the training needed to bolster my disease-state expertise, grantsmanship, and expand my analytical capabilities to ensure a smooth transition toward research independence.

项目摘要 肝脏和肾脏是葡萄糖生物合成与线粒体耦合的主要器官 代谢。先前的研究表明，营养不良会加速全身葡萄糖发生 （GNG）和柠檬酸周期（CAC）活性。先前研究的局限性是独特的 肝脏和肾脏对全身GNG和CAC通量的贡献很难解散 体内。无法从肾脏代谢通量中辨别肝素是一个显着差距 知识，因为肥胖可能不仅会导致脂质的生态积累，而且还会引起“异位” 重新分布的谷杆发育功能，使肾脏压力不成比例。我们假设 肾脏GNG和CAC活性在物体中的升高不成比例，这有助于 全身葡萄糖代谢的失调并促进线粒体功能障碍和氧化 肾脏的组织损伤。该提议的科学目的是（i）确定是否是否 肥胖的逐步发展不成比例地影响肾脏谷胱甘肽和氧化 代谢，（ii）评估肾脏上的糖原性超负荷是否会加速氧化物代谢 和肥胖期间的压力，（iii）识别SGLT2抑制剂治疗的代谢机制 在体内降低肝肾脂毒性。我们项目的目的将使用小说来实现 代谢通量建模系统同时决定糖原和氧化代谢 体内肝脏和肾脏中的通量。这项工作具有创新性，因为它研究了病因和 通过多器官通量的镜头治疗代谢疾病，同时专注于 葡萄糖（DYS）调节的研究方面。这很重要，因为它将识别特定器官 可以更好地靶向改善血糖控制并减少肾脏损害的代谢节点 和肝脏。这个K01项目的结果，我的心理委员会每个成员的独特专业知识， 范德比尔特大学的糖尿病研究基础设施将被利用以实现我的职业生涯 独立职业的目标，研究糖尿病肾脏疾病中的代谢调节和 降血糖反调节。因此，该项目将职业发展计划与 需要培训来增强我的疾病状态专业知识，授予技巧并扩展我的分析 确保平稳过渡到研究独立性的能力。