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.

项目摘要 美国退伍军人中肥胖症的流行率很高，并且与重大的医疗保健负担有关。 美国退伍军人事务部（VA）估计有78％的退伍军人是肥胖或超重，这是 估计占美国成年人口的35％估计35％。减肥手术目前是 持续体重减轻的最有效治疗方法。减肥手术干预，例如垂直袖子 与 常规的减肥疗法。但是，随着减肥手术的使用增加，也有更大的 意识到其并发症，例如骨质减少症（骨骼质量损失）和肝病的发展 对于一部分患者。我们VSG啮齿动物模型的初步数据导致我们假设肠道本人 成纤维细胞增长因子15/19（FGF15/19，小鼠/人类直系同源物）作为VSG效应的潜在介体。 FGF15/19在小肠的回肠肠上皮细胞中表达，并在后期释放 滥用胆汁酸。小鼠的血浆FGF19水平和回肠FGF15表达大大增加 在VSG之后。我们感觉到使用我们的新颖诱导性VSG的效果也需要测试FGF15是否也需要 肠特异性FGF15（FGF15INT-KO）鼠标模型。令我们惊讶的是，FGF15INT-KO VSG小鼠发育骨骼 VSG后的肌肉损失。此外，FGF15INT-KO小鼠不会显示出提高的葡萄糖耐受性，并且具有 VSG后肝胆固醇升高。 VSG后缺乏FGF15也会显着升高 血浆胆汁酸水平，包括有毒疏水性胆汁酸的显着增加。这是我们的数据暗示 增加FGF15对于限制VSG的有害作用至关重要 生理健康的范围。该项目的总体目标是检验FGF15是关键的假设 影响瘦肌肉和骨骼质量，肝脂质和葡萄糖的肠肝循环的调节剂 VSG之后的代谢。这些研究提出了一种调节患者胆汁酸信号的新机制 经历了VSG并发展骨骼和肌肉损失和肝脏损害的人。了解病因 这些并发症和开发潜在的治疗选择将改善VSG患者的护理。 Bozadjieva Kramer博士是大学外科科的博士后研究员 密歇根州。她在体外，体内和体内肥胖模型和2型的体内有丰富的经验 糖尿病。密歇根大学的Randy Seeley博士和Robert O'Rourke博士将提供主要基础 奖项期间分别是科学和临床科学心态。职业发展活动将 利用密歇根大学和安的卓越研究环境和资源 Arbor VA医疗中心。 Bozadjieva Kramer博士的职业和研究发展也将由 有积极进取的指导委员会，其中包括Drs。艾米·罗斯伯格（Amy Rothberg），奥蒙德·A·麦克杜格（Ormond A. F. Burant和Rohit Kohli。 Bozadjieva Kramer博士将利用各种培训活动来增强她的经验，知识和技能 多个领域，包括临床研究和代谢组学领域的技术和概念知识，研究 减肥手术，肠肝脏生理学，领导力，实验管理，有效的啮齿动物模型的技能 沟通和心理化的年轻科学家。该提案执行的培训和知识 将为Bozadjieva Kramer博士的未来研究指示奠定基础 在减肥手术的代谢作用中，肠肝轴以及为自己开始的培训提供了培训 独立研究计划。