Effect of surgical and pharmacological obesity treatments on hepatic fat, energy flux, and mitochondria

手术和药物肥胖治疗对肝脂肪、能量通量和线粒体的影响

基本信息

批准号：
10606390
负责人：
Kelly Fuller
金额：
$ 7.16万
依托单位：
UNIVERSITY OF COLORADO DENVER
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：
2023-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10606390
关键词：
Adolescence Adolescent Adult Agonist Body Weight decreased Body mass index Child Citric Acid Cycle Clinical Clinical Research Clinical Trials Colorado Coupling Data Diabetes Mellitus Diet Disease Event Family Fatty acid glycerol esters Foundations Functional disorder Future GCG gene GLP-I receptor Gastrectomy Gluconeogenesis Glucose Glycerol Goals Health Hepatic Human Hypergravity Impairment Institution Intervention Investigation Isotopes K-Series Research Career Programs Label Learning Life Style Modification Liver Liver Mitochondria Liver diseases Magnetic Resonance Imaging Maintenance Measures Medical Mentorship Metabolic Metabolic Diseases Metabolism Methods Mitochondria Molecular Morbid Obesity Mus Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Operative Surgical Procedures Oral Oral Administration Outcome Overnutrition Pathogenesis Pathogenicity Patients Pharmacological Treatment Physical activity Polycystic Ovary Syndrome Population Prevalence Research Research Technics Resolution Respiration Risk Rodent Model Science Scientist Serum Signal Transduction Spirometry Statistical Models Symptoms Targeted Research Testing Therapeutic Tissues Tracer Training Translational Research Triglycerides Universities Work Youth adult obesity bariatric surgery biological sex career cell injury chronic liver disease clinical trial implementation comorbidity disease diagnosis disorder risk experience glucose production high risk human model improved inorganic phosphate insight intrahepatic lifestyle intervention lipidomics liver inflammation liver metabolism mitochondrial metabolism mortality mouse model non-alcoholic fatty liver disease nonalcoholic steatohepatitis obesity treatment peer pharmacologic pre-clinical respiratory responders and non-responders response skills socioeconomics stable isotope translational research program translational scientist very low density lipoprotein triglyceride

项目摘要

PROPOSAL SUMMARY (ABSTRACT) Research Background and Impact: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disease worldwide and leads to early mortality. Because adolescent NAFLD largely presents as asymptomatic, research should focus on adolescents at particularly high-risk for disease, which includes those with extreme obesity and/or polycystic ovary syndrome (PCOS). The only approved treatment for NAFLD is lifestyle intervention, yet feasibility and long-term maintenance is extremely challenging in youth. Surgical and pharmacological obesity interventions have been explored for treatment of NAFLD in adults, with emerging data suggesting vertical sleeve gastrectomy (VSG) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve NAFLD. Data from both adults and pre-clinical rodent models suggest that aberrant hepatic mitochondria and hepatic energy flux are critically involved in the pathogenesis of NAFLD, but whether these underlying mechanisms are responsive to therapy remains unknown. Further, these surgical and pharmacological treatments have not been studied in youth. Therefore, the goal of this proposal is to use a translational research approach to evaluate hepatic fat, metabolism, and mitochondrial function before and after surgical (VSG) and pharmacological (GLP1-RA) interventions in youth (and mice for VSG) at high risk for NAFLD due to obesity and/or PCOS. We will assess hepatic fat via liver MRI, use oral glycerol isotope tracers and serum and hepatic isotopomer analysis via NMR to quantify and describe dynamics of hepatic metabolism, and measure mitochondria function via high resolution respirometry of fresh liver tissue and non-invasive 31Phos-MRS for intrahepatic phosphate concentrations. These studies will provide excellent mechanistic insight into emerging therapeutic options and will improve the immediate and long-term health of at-risk youth. Candidate and Training: My long-term career goal is to be an independent, academic scientist with a translational research program focused on understanding the molecular signaling events underlying the pathophysiology of metabolic disease, with a focus on NAFLD. I have extensive experience in pre-clinical mouse models but to become an independent translational investigator, I need training in clinical trial research. These proposed studies will expand my research capabilities to include clinical trial implementation, stable isotope tracers, and 31Phos MRS. I will also expand my pre-clinical and bench science research techniques to include mouse survival surgery and lipidomics. The opportunities provided by my institution (University of Colorado Anschutz Medical Campus) and by my mentorship team (Drs. Melanie Cree-Green, Darleen Sandoval, Jane Reusch, Craig Malloy, Bryan Bergman, Laura Pyle) will provide excellent training in integrative hepatic metabolism.

提案摘要（摘要）研究背景和影响：非酒精性脂肪肝病（NAFLD）是肝病的主要原因在全球范围内，导致早期死亡率。因为青少年的NAFLD在很大程度上是无症状的，所以研究应该专注于特别高风险的疾病的青少年，其中包括极端肥胖症的疾病和/或多囊卵巢综合征（PCOS）。 NAFLD唯一批准的治疗方法是生活方式干预，但在青年中，可行性和长期维护极为挑战。手术和药理肥胖已经探索了成人NAFLD治疗的干预措施，并有新兴的数据表明垂直套筒胃切除术（VSG）和胰高血糖素样肽-1受体激动剂（GLP-1 RA）改善了NAFLD。来自两者的数据成人和临床前啮齿动物模型表明，异常的肝线粒体和肝能量是与NAFLD的发病机理有关，但是这些潜在的机制是否反应治疗仍然未知。此外，这些手术和药理治疗尚未在青年。因此，该提案的目的是使用翻译研究方法来评估肝脂肪，外科（VSG）和药理学（GLP1-RA）之前和之后的代谢和线粒体功能（GLP1-RA）由于肥胖和/或PCOS，对NAFLD高风险的年轻人（和VSG的小鼠）进行干预措施。我们将评估肝脂肪通过肝脏MRI，使用口服甘油同位素示踪剂和血清以及肝同位素分析通过NMR 量化和描述肝代谢的动力学，并通过高分辨率测量线粒体功能肝内磷酸盐浓度的新鲜肝组织和非侵入性31phos-MR的呼吸测定法。这些研究将为新兴的治疗选择提供出色的机械洞察力，并将改善高危青年的立即和长期健康。候选人和培训：我的长期职业目标是成为一名独立的学术科学家研究计划的重点是了解病理生理基础的分子信号事件代谢疾病，重点是NAFLD。我在临床前的鼠标模型中有丰富的经验，但成为独立的翻译研究者，我需要在临床试验研究中进行培训。这些提议研究将扩大我的研究能力，包括临床试验实施，稳定的同位素示踪剂和 31phos Mrs。我还将扩展临床前和台式科学研究技术以包括鼠标生存手术和脂肪组学。我的机构提供的机会（科罗拉多大学安索斯大学医学校园）和我的指导团队（Melanie Cree-Green博士，Darleen Sandoval，Jane Reusch，Craig Malloy， Bryan Bergman，Laura Pyle）将在综合肝代谢方面提供出色的培训。