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

摘要 在这份指导职业发展奖(K23)的提案中，这位候选人建议巩固一个基本的 他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 成为肠内分泌学术权威L--肥胖饱腹感的细胞调控。候选人 旨在获得坚实的临床翻译科学基础，并获得一套新颖的补充 具备从事胃肠道食物摄入量调节的独立研究生涯所需的技能。 对于人类肥胖的病理生理学理解受到患者表型的异质性和 多种致病机制。这些因素导致了高度可变的个体间体重减轻 对所有干预措施作出反应。最近，我们发现肥胖的一个亚群显著减少。 饱腹感(定义为缺乏饱腹感或迅速恢复饥饿)。我们的初步数据显示， 除了饭后饱腹感降低外，与其他肥胖者相比，这些人 表型，餐后分泌的GI饱腹感激素GLP-1和PYY水平非常低 肠内分泌(EE)L细胞。低水平的饱腹感激素PYY，可能还有其他EE细胞 Products表明，卡路里摄入量的增加源于肠道激素的不足，而这 表型可概括为“饥饿的肠道”。次优的EE细胞功能，它可以通过 EE细胞自身合成或分泌的改变，或分子管腔浓度的降低 通常刺激EE细胞的物质，如氨基酸、胆汁酸或短链脂肪酸。我们的预赛 研究结果还表明，这些个体体内可替代鲁米那胆汁酸的成纤维细胞生长因子-19水平较低。 集中精神。 在这些初步研究的基础上，了解导致 EE信号的缺陷导致肥胖的“饥饿的肠道”表型。为了测试这一概念，我们 提出了以下两个目标：1)研究饥饿肠道表型的发生机制 并将这些发现与其他肥胖表型和正常体重的健康对照组进行比较。2) Roux-in-y术后通过增加肠内分泌细胞功能和分泌来恢复正常饱腹感 胃旁路手术或鲁米那胆汁酸治疗的反应。这些发现将为 为在未来的R01应用中进一步研究“饥饿肠道”表型奠定了基础。这项工作将是 在梅奥诊所内的学术培养环境中进行，并得到 胃肠病学。候选人将由一个强大的指导委员会(Michael Camilleri博士、 尼古拉斯·拉鲁索和禤浩焯·贝拉)。作为这项工作的结果，候选人将极大地提高我们的 了解EE细胞在人类肥胖中的功能并发展他的职业生涯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.