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

项目摘要 美国退伍军人中肥胖的患病率很高，并与大量的医疗保健负担相关。 美国退伍军人事务部（VA）估计，78%的退伍军人肥胖或超重， 远高于美国非退伍军人成年人口的估计35%。减肥手术目前是 最有效的持续减肥方法。减肥手术干预，如Vertical Sleeve 胃切除术（VSG）也能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，随着减肥手术的使用越来越多， 了解其并发症，如骨质减少（骨量丢失）和肝脏疾病的发展 for a subset子集of patients患者.我们的啮齿动物VSG模型的初步数据使我们假设肠道激素 成纤维细胞生长因子15/19（FGF 15/19，小鼠/人直系同源物）作为VSG效应的有效介质。 FGF 15/19在小肠的回肠肠上皮细胞中表达，并在餐后响应于胃肠道的刺激而释放。 胆汁酸吸收人血浆FGF 19水平和小鼠回肠FGF 15表达显著增加 在VSG之后。我们试图用我们的新的诱导型细胞因子来测试FGF 15是否也是VSG作用所必需的。 精氨酸特异性FGF 15（FGF 15 INT-KO）小鼠模型。令我们惊讶的是，FGF 15 INT-KO VSG小鼠的骨骼发育 以及VSG后的肌肉萎缩此外，FGF 15 INT-KO小鼠未显示出改善的葡萄糖耐量，并且具有显著的糖耐量。 VSG后肝胆固醇升高。VSG后FGF 15的缺乏也导致VSG后FGF 15的显著升高。 血浆胆汁酸水平，包括毒性疏水胆汁酸的显著增加。因此，我们的数据表明， 增加的FGF 15是通过将胆汁酸保持在一定范围内来限制VSG的有害作用所必需的。 生理健康的范围。该项目的总体目标是测试FGF 15是一个关键的假设。 影响瘦肌肉和骨质、肝脏脂质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 进行了VSG并出现骨骼和肌肉损失以及肝脏损伤的患者。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。 博士Bozadjieva克雷默是密歇根大学外科系的博士后研究员。 密歇根她在肥胖和2型糖尿病的体外、离体和体内模型方面有丰富的工作经验。 糖尿病密歇根大学的Randy塞利博士和Robert O 'Rourke博士将提供基本的 科学和临床科学导师，分别在颁奖期间。职业发展活动将 利用密歇根大学和安 Arbor VA医疗中心Bozadjieva克雷默博士的职业生涯和研究发展也将得到促进， 高度积极的指导委员会，其中包括博士艾米罗斯伯格，奥蒙德A。查尔斯·麦克杜格尔 F. Burant和Rohit Kohli。 博士博扎杰娃·克雷默将利用各种培训活动来增强她在以下方面的经验、知识和技能 包括临床研究和代谢组学的技术和概念知识，研究 在减肥手术，肠肝生理学，领导，实验室管理，有效的啮齿动物模型的技能 沟通和指导年轻科学家。本建议书执行过程中的培训和知识 将为Bozadjieva克雷默博士未来的研究方向奠定基础， 肠肝轴在减肥手术的代谢影响，以及提供培训，开始自己的 独立研究计划。

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.