Mechanisms of Enteroendocrine Cell Adaptation to High Fat Diet in Zebrafish

摘要 肠内分泌细胞是肠上皮的重要感觉细胞，分泌多种激素 在人类代谢疾病的许多失调过程中起重要作用，如饱腹感信号和葡萄糖 体内平衡EEC根据其主要激素分为亚型。作为肠内分泌 激素具有不同的，有时是拮抗性的代谢作用，这种细分使微调 对各种饮食刺激作出反应的新陈代谢控制。许多报告显示， 在患有肥胖症和代谢疾病的人类和小鼠中，平衡被扰乱， EEC亚型分布和循环EEC激素水平。尽管有这些进步，我们仍然没有 了解调节EEC适应饮食的过程以及这些过程在EEC中的差异 亚型为了填补这些知识空白，我的导师的实验室最近建立了斑马鱼作为模型 研究EEC生理学的系统。斑马鱼幼鱼的光学透明性使活体成像能够观察 EEC在体内和真实的时间内的适应性，在活体哺乳动物中无法获得的分辨率水平。利用斑马鱼， 我们发现了一种新的现象，即EEC形态的急剧变化和EEC营养物质的减少， 高脂喂养后的敏感性，我们称之为“EEC沉默”。本提案的目的是了解 高脂喂养诱导的EEC适应的分子和细胞机制。具体来说，我会 测试来自肠上皮细胞的脂质信号和来自抑制性EEC亚型的激素信号的贡献 介导高脂喂养诱导的EEC沉默。这项工作预计将大大推动我们的 了解肠道适应饮食的基本生理学，对人类具有重要意义 代谢性疾病

ABSTRACT Enteroendocrine cells (EECs) are key sensory cells in the intestinal epithelium that secrete diverse hormones important in many processes dysregulated in metabolic disease in humans, such as satiety signaling and glucose homeostasis. EECs are divided into subtypes based on their predominant hormone. As enteroendocrine hormones have different and sometimes antagonistic metabolic effects, this subdivision enables finely-tuned control of metabolism in response to a variety of dietary stimuli. Many reports have shown that this careful balance is disturbed in humans and mice with obesity and metabolic disease, including changes in the number of EECs, EEC subtype distribution, and circulating EEC hormone levels. Despite these advances, we still do not understand the processes that regulate EEC adaptation to diet and how these processes may differ across EEC subtypes. To address these gaps in knowledge, my mentors’ labs recently established zebrafish as a model system for studying EEC physiology. The optical transparency of larval zebrafish enables live imaging to observe EEC adaptations in vivo and in real time, a level of resolution not available in live mammals. Using the zebrafish, we discovered a novel phenomenon of acute change in EEC morphology and reduction in EEC nutrient sensitivity after high fat feeding we named “EEC silencing.” The objective of this proposal is to understand the molecular and cellular mechanisms underlying this high fat feeding-induced EEC adaptation. Specifically, I will test the contributions of lipid signaling from enterocytes and hormone signaling from an inhibitory EEC subtype in mediating high fat feeding-induced EEC silencing. This work is expected to significantly advance our understanding of the fundamental physiology of intestinal adaptation to diet with important implications for human metabolic disease.