In vivo hepato-renal metabolic flux dysregulation in obesity

项目摘要 肝脏和肾脏是葡萄糖生物合成与线粒体结合的主要器官 新陈代谢.以前的研究表明，营养过剩会加速全身的新陈代谢。 (GNG)和体内柠檬酸循环（CAC）活性。先前研究的一个局限性是， 肝脏和肾脏对全身GNG和CAC通量的贡献一直难以解开 in vivo.无法区分肝脏和肾脏的代谢通量代表了一个重大差距， 知识，因为肥胖不仅可能导致脂质的异位积聚，而且可能导致“异位”脂质积聚。 肾功能不成比例地受到压力。我们假设 肾GNG和CAC活性在肥胖者中不成比例地升高，这有助于 全身葡萄糖代谢失调，并促进线粒体功能障碍和氧化 肾脏组织损伤本提案的科学目的是：（一）确定 肥胖的进行性发展不成比例地影响肾脏的致炎和氧化 （ii）评估肾脏上的致炎性超负荷是否加速氧化代谢 和肥胖期间的压力，以及（iii）确定SGLT 2抑制剂治疗 降低体内肝肾脂毒性。我们项目的目标将通过一部小说来实现， 代谢通量建模系统，其同时确定产气代谢和氧化代谢 体内肝脏和肾脏中的通量。这项工作是创新的，因为它检查了病因， 通过多器官通量组学的透镜治疗代谢性疾病， 葡萄糖（dys）调节的未充分研究的方面。这很重要，因为它将识别器官特异性 可能更好地靶向改善血糖控制和减少肾脏损伤的代谢节点 和肝脏。从这个K01项目的结果，我的指导委员会的每个成员的独特的专业知识， 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 目的是研究糖尿病肾病的代谢调节， 低血糖反调节。因此，该项目将职业发展计划与 培训需要加强我的疾病状态的专业知识，格兰特，并扩大我的分析 确保向研究独立平稳过渡的能力。

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.