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

项目总结 美国退伍军人中肥胖率很高，并与巨大的医疗负担有关。 美国退伍军人事务部(VA)估计，78%的退伍军人肥胖或超重，这是 远高于美国非退伍军人成年人口的35%。减肥手术目前是 对持续减肥最有效的治疗。减肥手术干预措施，如垂直袖子 胃切除术(VSG)也能更有效地改善患者的血糖控制和其他并发症 传统的减肥疗法。然而，随着减肥手术的使用越来越多，也有更大的 对其并发症的认识，如骨量减少(骨量丢失)和肝病的发展 适用于部分患者。来自我们的VSG啮齿动物模型的初步数据使我们假设胃肠激素 成纤维细胞生长因子15/19(FGF15/19，鼠/人同源基因)作为血管紧张素转换酶效应的有效中介。 FGF15/19在小肠的回肠肠上皮细胞中表达，并在餐后释放 胆汁酸吸收。人血浆FGF19水平和小鼠回肠FGF15表达水平显著升高 在VSG之后。我们试图使用我们的新型诱导物来测试VSG的效果是否也需要FGF15 肠特异性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术后肌力减退。此外，FGF15INT-KO小鼠没有表现出糖耐量的改善，而是 VSG后肝脏胆固醇升高。VSG后FGF15的缺乏也导致显著升高 血浆胆汁酸水平，包括毒性疏水性胆汁酸明显增加。因此，我们的数据表明 增加的FGF15对于限制VSG的有害影响至关重要，因为它将胆汁酸保持在 生理上健康的范围。这个项目的总体目标是测试FGF15是一个关键的 影响瘦肉、骨量、肝脂和血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的新机制。 他们接受了VSG，并出现了骨骼和肌肉丢失以及肝脏损伤。了解心绞痛的病因 这些并发症和开发潜在的治疗方案将改善对VSG患者的护理。 Bozadjieva Kramer博士是加州大学外科学系博士后研究员 密歇根州。她在肥胖症和2型肥胖的体外、体外和体内模型方面拥有丰富的工作经验。 糖尿病。密歇根大学的Randy Seeley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 充分利用密歇根大学和安大略分校卓越的研究环境和资源 阿博尔退伍军人医疗中心。Bozadjieva Kramer博士的职业生涯和研究发展也将得到 高度激励的指导委员会，其中包括艾米·罗斯伯格博士、奥蒙德·A·麦克杜加尔德博士、查尔斯·麦克杜加德博士 伯兰特和罗希特·科利。 Bozadjieva Kramer博士将利用各种培训活动来加强她在 几个领域，包括临床研究和代谢组学方面的技术和概念知识，研究 减肥手术啮齿动物模型的技能，肠肝生理学，领导力，实验室管理，有效 交流，并指导年轻科学家。本建议书执行过程中的培训和知识 将为Bozadjieva Kramer博士未来的研究方向奠定基础 肠肝轴在减肥手术中对新陈代谢的影响，以及为自己开始提供培训 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.