In vivo hepato-renal metabolic flux dysregulation in obesity

肥胖体内肝肾代谢通量失调

基本信息

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
项目类别：
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

项目摘要

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先前的研究表明，营养过剩会加速全身糖异生。 (GNG) 和柠檬酸循环 (CAC) 体内活性的局限性是其独特性。肝脏和肾脏对全身 GNG 和 CAC 通量的贡献一直难以理清无法区分肝脏和肾脏的代谢通量代表了显着的差距。众所周知，肥胖不仅会导致脂质异位堆积，还会导致“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。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该提案的科学目的是 (i) 确定是否存在肾脏组织损伤。肥胖的逐渐发展不成比例地影响肾糖异生和氧化代谢，(ii) 评估肾脏的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使用一种新颖的、同时确定糖原代谢和氧化代谢的代谢流建模系统这项工作是创新性的，因为它检查了病因和体内肝脏和肾脏的通量。通过多器官通量组学的视角治疗代谢性疾病，同时关注葡萄糖（dys）调节的未充分研究的方面很重要，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这个 K01 项目的结果，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因此，该项目将职业发展计划与低血糖反调节相结合。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。