Mechanisms of Enteroendocrine L-Cell Dysfunction and Bile Adaptations to Weight Loss

摘要 在这个辅导职业发展奖（K23）的建议，这位候选人建议巩固一个基本的 在博士和博士后工作期间获得的科学基础和临床研究，具有长期目标 成为肠内分泌L细胞调节肥胖饱腹感的学术权威。候选 旨在获得一个坚实的基础，在临床翻译科学和获得一套新的补充 在胃肠调节食物摄入方面的独立研究生涯所需的技能。 了解人类肥胖的病理生理学受到患者表型异质性的限制， 多种病因机制。这些因素导致了个体间体重减轻的高度可变性 对所有干预措施作出回应。最近，我们发现了一个肥胖亚群， 饱腹感（定义为缺乏饱腹感或饥饿感迅速恢复）。我们的初步数据显示， 除了减少饱胀感饭后，这些人相比，其他肥胖 表型，具有非常低的餐后水平的胃肠道饱腹感激素GLP-1和PYY， 肠内分泌（EE）L细胞。饱腹感激素PYY和可能的其他EE细胞的低水平 产品表明，增加的卡路里摄入量源于肠道激素的不足， 表型概括为“饥饿的肠道”。次优EE细胞功能，这可能是介导的 EE细胞自身的合成或分泌改变，或分子的管腔浓度降低 通常刺激EE细胞的物质，如氨基酸、胆汁酸或短链脂肪酸。我们的初步 结果还表明，这些个体的FGF-19水平较低，FGF-19是管腔胆汁酸的替代物 浓度. 基于这些初步研究，了解导致这些疾病的机制是至关重要的。 导致肥胖症的“饥饿肠道”表型的EE信号缺陷。为了验证这个概念，我们 提出以下两个目标：1）从基因水平研究饥饿肠道表型的机制， EE细胞，并将这些发现与其他肥胖表型和正常体重的健康对照进行比较。（二） 通过增加Roux-in-y术后患者的肠内分泌细胞功能和分泌来恢复正常饱腹感 胃旁路手术或对管腔胆汁酸治疗的反应。这些发现将提供 为在未来R 01应用中进一步研究“饥饿肠道”表型奠定了基础。这项工作将 在马约诊所的学术环境中进行，并得到 胃肠病学。候选人将由一个强大的指导委员会（迈克尔卡米莱里博士， Nicholas LaRusso和Adrian Vella）。作为这项工作的结果，候选人将大大提高我们的 了解EE细胞在人类肥胖中的功能，并将他的职业生涯发展成为一名独立的医生 科学家

ABSTRACT In this Mentored Career Development Award (K23) proposal, this candidate proposes to solidify a basic science foundation and clinical research acquired during his PhD and post-doctoral work with a long-term goal of becoming an academic authority in enteroendocrine L-cell regulation of satiety in obesity. The candidate aims to acquire a strong foundation in clinical translation science and to acquire a set of novel complementary skills necessary for an independent research career in gastrointestinal regulation of food intake. Understanding pathophysiology of human obesity is limited by the heterogeneity of patients' phenotype and multiple etiological mechanisms. These factors contribute to the highly variable inter-individual weight loss response to all interventions. Recently, we identified a sub-population of obesity with significantly decreased satiety (defined as lack of sensation of feeling full or rapid return of hunger). Our preliminary data shows that, in addition to decreased perception of fullness after a meal, these individuals, compared to other obesity phenotypes, have very low postprandial levels of the GI satiety hormones GLP-1 and PYY which are secreted by enteroendocrine (EE) L-cells. The low levels of the satiety hormone PYY and possibly other EE cell products suggests that the increased calorie intake originates from a deficit in the gut hormones, and this phenotype is summarized as a “hungry gut”. The suboptimal EE cell function, which could be mediated by altered synthesis or secretion by the EE cells themselves, or a decrease in luminal concentrations of molecules that normally stimulate EE cells, such as amino acids, bile acids, or short-chain fatty acids. Our preliminary results also suggest that these individuals have lower levels of FGF-19, a surrogate of the luminal bile acid concentration. Based on these preliminary studies, it is essential to understand the mechanisms that are responsible for the deficient EE signals that lead to the “hungry gut” phenotype of obesity. To test this concept, we propose the following two aims: 1) to study the mechanism of the hungry gut phenotype down to the level of the EE cells, and compare these findings to other obesity phenotypes and normal weight, healthy controls. 2) To restore normal satiety by increasing enteroendocrine cell function and secretion in patients after Roux-in-y gastric bypass surgery or in response to treatment with luminal bile acids. These findings will provide the foundation for further studies of the “hungry gut” phenotype in a future R01 application. This work will be performed in an academically nurturing environment within Mayo Clinic and with full support of the Division of Gastroenterology. The candidate will be guided by a strong mentorship committee (Drs. Michael Camilleri, Nicholas LaRusso and Adrian Vella). As a result of this work, the candidate will significantly advance our understanding of EE cell function in human obesity and develop his career into an independent physician scientist.