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偶联的主要器官。 新陈代谢。先前的研究表明，营养过剩会加速全身的糖异生 (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 肝和肾对全身GNG和CAC通量的贡献一直难以厘清 在活体内。无法区分肝脏和肾脏的代谢流量代表着一个显著的差距 知识，因为肥胖不仅可能导致脂肪的异位堆积，而且还会导致 “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 肥胖者肾脏GNG和CAC活性不成比例地升高，这是导致 全身糖代谢失调，促进线粒体功能障碍和氧化 肾脏的组织损伤。这项提议的科学目的是：(I)确定 肥胖的进行性发展对肾脏糖异生和氧化的影响不成比例 代谢，(Ii)评估肾脏上的糖异生超负荷是否会加速氧化代谢 和肥胖过程中的应激，以及(Iii)确定SGLT2抑制剂治疗的代谢机制(S 降低体内肝肾脂肪毒性。我们项目的目标将通过一部小说来实现， 同时确定糖异生代谢和氧化代谢的代谢通量模拟系统 体内肝和肾中的流量。这项工作具有创新性，因为它研究了病原学和 从多器官流体学的视角治疗代谢性疾病 对葡萄糖(Dys)调节的研究不足。它具有重要意义，因为它将识别特定的器官 代谢节点可能更有针对性地改善血糖控制和减少肾脏损害 还有肝脏。这个K01项目的结果，我的指导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用来实现我的职业生涯 研究糖尿病肾病代谢调节的独立职业目标和 降血糖反调节。因此，该项目将职业发展计划与 需要进行培训，以增强我的疾病状态专业知识、勇气和分析能力 确保向研究独立平稳过渡的能力。