Mechanisms of Enteroendocrine Cell Adaptation to High Fat Diet in Zebrafish

摘要 肠内分泌细胞(EECS)是肠上皮细胞中的重要感觉细胞，分泌多种激素。 在人类代谢性疾病中的许多过程中都很重要，如饱腹感信号和葡萄糖 动态平衡。EECs根据其主要激素被分为亚型。作为肠道内分泌 荷尔蒙有不同的，有时甚至是拮抗的新陈代谢作用，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。许多报告都表明，这一谨慎 患有肥胖症和代谢性疾病的人类和小鼠的平衡被扰乱，包括数量的变化 EECS、EEC亚型分布和循环EEC激素水平。尽管取得了这些进展，但我们仍然没有 了解调节EEC对饮食的适应的过程，以及这些过程在EEC之间可能有何不同 子类型。为了解决这些知识上的差距，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。斑马鱼幼体的光学透明性使活体成像能够观察到 EEC在活体和实时适应，这是活体哺乳动物所不具备的分辨率水平。使用斑马鱼， 我们发现了一种新的现象，即EEC形态急剧变化和EEC营养减少 高脂喂养后的敏感性，我们称之为“EEC沉默”。这项建议的目的是了解 这种高脂肪喂养诱导的EEC适应的分子和细胞机制。具体来说，我会 检测来自肠上皮细胞的脂质信号和来自抑制性EEC亚型的激素信号的作用 在介导高脂饮食诱导的EEC沉默方面。这项工作有望大大推进我们的 理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.