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.

项目概要 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，营养过剩会加速全身糖异生 （GNG）和体内柠檬酸循环（CAC）活性。先前研究的一个局限性是，独特的 肝脏和肾脏对全身 GNG 和 CAC 通量的贡献一直难以理清 体内。无法区分肝脏和肾脏的代谢通量，这表明在 肥胖不仅可能导致脂质异位堆积，而且可能导致“异位脂肪堆积”。 糖异生功能的重新分配“对肾脏造成不成比例的压力。我们假设 肥胖者的肾脏 GNG 和 CAC 活性不成比例地升高，这导致 全身葡萄糖代谢失调，促进线粒体功能障碍和氧化 肾脏组织损伤。该提案的科学目标是 (i) 确定是否 肥胖的进行性发展不成比例地影响肾糖异生和氧化 代谢，(ii) 评估肾脏糖异生超负荷是否加速氧化代谢 和肥胖期间的压力，以及 (iii) 确定 SGLT2 抑制剂治疗的代谢机制 降低体内肝肾脂毒性。我们项目的目标将通过一种新颖的、 同时确定糖异生和氧化代谢的代谢流建模系统 体内肝脏和肾脏的通量。这项工作具有创新性，因为它研究了病因并 通过多器官通量组学的视角治疗代谢疾病，同时关注 葡萄糖（dys）调节方面的研究不足。它很重要，因为它将识别器官特异性 可能更有针对性地改善血糖控制并减少肾脏损伤的代谢节点 和肝脏。这个 K01 项目的成果，我的指导委员会每位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有助于实现我的职业生涯 研究糖尿病肾病代谢调节的独立职业目标 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、资助能力并扩展我的分析能力 确保向研究独立平稳过渡的能力。