The role of intestinal-derived FGF15/19 during obesity and rapid weight loss

肠源性 FGF15/19 在肥胖和快速减肥过程中的作用

• 批准号: 10364480
• 负责人: Nadejda Bozadjieva Kramer
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10364480
• 关键词: Adult; Area; Award; Awareness; Basic Science; Bile Acid Biosynthesis Pathway; Bile Acids; Binding; Blood Circulation; Body Composition; Body Weight; Body Weight decreased; Bone Density; Caloric Restriction; Cardiovascular Diseases; Caring; Cholesterol; Clinical Research; Clinical Sciences; Communication; Complex; Data; Development; Diet; Enterocytes; Enterohepatic Circulation; Environment; Etiology; FGF19 gene; FGFR4 gene; Fatty Liver; Fibrinogen; Fibroblast Growth Factor; Foundations; Future; Gastrectomy; Genes; Glucose Clamp; Glucose Intolerance; Goals; Greater curvature of stomach; Health; Healthcare; Hepatic; Hormones; Human; Hydrophobicity; In Vitro; Insulin Resistance; Intervention; Intestines; Knockout Mice; Knowledge; Leadership; Ligands; Liver; Liver diseases; Mediator of activation protein; Medical center; Mentors; Mentorship; Metabolic; Metabolic Diseases; Michigan; Morbid Obesity; Mus; Muscular Atrophy; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Obesity; Operative Surgical Procedures; Organism; Orthologous Gene; Osteopenia; Overweight; Patient Selection; Patients; Pharmacology; Physiological; Physiology; Plasma; Population; Prevalence; Production; Public Health; Receptor Signaling; Regulation; Research; Research Project Grants; Resources; Risk; Rodent Model; Role; Scientist; Signal Pathway; Signal Transduction; Small Intestines; Testing; Therapeutic Intervention; Thinness; Toxic effect; Training; Training Activity; Travel; United States Department of Veterans Affairs; Universities; Venous; Veterans; Work; absorption; bariatric surgery; bone loss; bone mass; career development; comorbidity; diagnostic tool; effective therapy; experience; farnesoid X-activated receptor; glucose metabolism; glucose production; glucose tolerance; glucose uptake; glycemic control; human disease; ileum; improved; in vivo Model; innovation; lipid metabolism; liver ablation; liver injury; metabolomics; military veteran; mouse model; muscle form; novel; obese patients; patient subsets; preclinical study; preservation; prevent; programs; protective effect; receptor; research and development; response; side effect; skills; transcription factor; weight loss intervention

PROJECT SUMMARY The prevalence of obesity among US Veterans is high and associated with a substantial healthcare burden. The US Department of Veteran Affairs (VA) estimated 78% of Veterans are obese or overweight, which is much higher than the estimated 35% of the non-Veteran US adult population. Bariatric surgery is currently the most effective treatment for sustained weight loss. Bariatric surgery interventions, such as Vertical Sleeve Gastrectomy (VSG), also improve glycemic control and other comorbidities in patients more effectively than conventional weight loss therapies. However, with the rising use of bariatric surgery, there is also greater awareness of its complications, such as the development of osteopenia (loss in bone mass) and liver disease for a subset of patients. Preliminary data from our rodent model of VSG led us to hypothesize the gut hormone Fibroblast-Growth Factor 15/19 (FGF15/19, mouse/human ortholog) as a potent mediator for VSG effects. FGF15/19 is expressed in ileal enterocytes of the small intestine and is released postprandially in response to bile acid absorption. Plasma FGF19 levels in humans and ileal FGF15 expression in mice greatly increased after VSG. We sought to test whether FGF15 is also required for the effects of VSG using our novel inducible intestine-specific FGF15 (FGF15INT-KO) mouse model. To our surprise, FGF15INT-KO VSG mice develop bone and muscle loss after VSG. Additionally, FGF15INT-KO mice do not show improved glucose tolerance and have increased hepatic cholesterol after VSG. The lack of FGF15 after VSG also results in markedly elevated plasma bile acid levels, including significant increase in toxic hydrophobic bile acids. Thus, our data suggest that increased FGF15 is essential to limit the deleterious effects of VSG by keeping bile acids within a physiologically healthy range. The overall goal of this project is to test the hypothesis that FGF15 is a critical regulator of enterohepatic circulation that impacts lean muscle and bone mass, hepatic lipids and glucose metabolism after VSG. These studies propose a novel mechanism for regulating bile acid signaling in patients who have undergone VSG and develop bone and muscle loss and liver damage. Understanding the etiology of these complications and developing potential treatment options will improve care for VSG patients. Dr. Bozadjieva Kramer is a Postdoctoral Research Fellow in the Department of Surgery at the University of Michigan. She has extensive experience working with in vitro, ex vivo and in vivo models of obesity and type 2 diabetes. Dr. Randy Seeley and Dr. Robert O’Rourke at the University of Michigan will provide primary basic science and clinical science mentorship, respectively, during the award. The career development activities will take advantage of the exceptional research environment and resources at the University of Michigan and Ann Arbor VA Medical Center. Dr. Bozadjieva Kramer’s career and research development will also be facilitated by highly motivated Mentoring Committee, which includes Drs. Amy Rothberg, Ormond A. MacDougald, Charles F. Burant and Rohit Kohli. Dr. Bozadjieva Kramer will use various training activities to strengthen her experience, knowledge, and skills in several areas, including technical and conceptual knowledge in clinical research and metabolomics, research skills in rodent models of bariatric surgery, enterohepatic physiology, leadership, lab management, effective communication, and mentoring young scientists. The training and knowledge from execution of this proposal will lay the foundation for Dr. Bozadjieva Kramer’s future research directions in dissecting the role of enterohepatic axis in the metabolic effects of bariatric surgery, as well as providing training for starting her own independent research program.

项目概要 美国退伍军人中肥胖的患病率很高，并且与沉重的医疗负担有关。 美国退伍军人事务部 (VA) 估计 78% 的退伍军人肥胖或超重，这 远高于估计的 35% 的美国非退伍军人成年人口。目前减肥手术是 持续减肥的最有效治疗方法。减肥手术干预措施，例如垂直袖套 胃切除术 (VSG) 也比胃切除术更有效地改善患者的血糖控制和其他合并症 传统的减肥疗法。然而，随着减肥手术的日益普及，也出现了更大的问题。 对其并发症的认识，例如骨质减少（骨质流失）和肝脏疾病的发生 对于一部分患者。我们的 VSG 啮齿动物模型的初步数据使我们推测肠道激素 成纤维细胞生长因子 15/19（FGF15/19，小鼠/人直系同源物）作为 VSG 效应的有效介质。 FGF15/19 在小肠的回肠肠细胞中表达，并在餐后响应 胆汁酸吸收。人类血浆 FGF19 水平和小鼠回肠 FGF15 表达大幅增加 VSG 之后。我们试图使用我们的新型诱导剂来测试 FGF15 是否也是 VSG 效果所必需的 肠道特异性 FGF15 (FGF15INT-KO) 小鼠模型。令我们惊讶的是，FGF15INT-KO VSG 小鼠发育出骨骼 VSG 后肌肉损失。此外，FGF15INT-KO 小鼠没有表现出葡萄糖耐量的改善，并且具有 VSG 后肝脏胆固醇增加。 VSG 后缺乏 FGF15 也会导致显着升高 血浆胆汁酸水平，包括有毒疏水性胆汁酸显着增加。因此，我们的数据表明 增加 FGF15 对于通过将胆汁酸保持在一定范围内来限制 VSG 的有害影响至关重要 生理健康范围。该项目的总体目标是检验 FGF15 是一个关键的假设 影响瘦肌肉和骨量、肝脂和葡萄糖的肠肝循环调节剂 VSG 后的代谢。这些研究提出了一种调节患者胆汁酸信号传导的新机制 接受 VSG 并出现骨骼和肌肉损失以及肝损伤的人。了解病因 这些并发症和开发潜在的治疗方案将改善 VSG 患者的护理。 Bozadjieva Kramer 博士是莫斯科大学外科系的博士后研究员 密歇根州。她在肥胖和 2 型的体外、离体和体内模型方面拥有丰富的经验 糖尿病。密歇根大学的 Randy Seeley 博士和 Robert O’Rourke 博士将提供初级基础课程 颁奖期间分别提供科学和临床科学指导。职业发展活动将 利用密歇根大学和安大学卓越的研究环境和资源 阿伯退伍军人医疗中心。 Bozadjieva Kramer 博士的职业生涯和研究发展也将得到促进 积极主动的指导委员会，其中包括博士。艾米·罗斯伯格、奥蒙德·A·麦克杜格尔、查尔斯 F. Burant 和罗希特·科利。 Bozadjieva Kramer 博士将利用各种培训活动来加强她在以下方面的经验、知识和技能： 多个领域，包括临床研究和代谢组学、研究中的技术和概念知识 减肥手术啮齿动物模型技能、肠肝生理学、领导力、实验室管理、有效 交流和指导年轻科学家。执行本提案的培训和知识 将为 Bozadjieva Kramer 博士未来的研究方向奠定基础，剖析 肠肝轴在减肥手术代谢影响中的作用，并为她开始自己的手术提供培训 独立研究计划。