Glutamatergic neurotransmission in gut neuropod cells

摘要 尽管过量摄入糖和代谢综合征之间存在明显的联系，但肠道感觉和 将糖的存在传达给大脑仍然是未知的。研究表明，人们倾向于 糖并不取决于它们在口腔中的甜味，而是取决于它们进入肠道的情况。 因此，了解肠道如何传递有关摄入糖类的信息可能会开辟一条新的道路 用于治疗代谢性疾病的药物疗法。感知肠道中营养物质的机制是 被认为与肠道内分泌细胞释放的多肽的较慢的旁分泌和内分泌作用有关。 近年来，很明显，除了典型的旁分泌功能外，肠内分泌还具有 细胞也与肠黏膜和结肠粘膜下的神经形成突触。这些肠道上皮细胞 形成突触的细胞被称为神经足细胞。我们的总体假设是谷氨酸能神经足细胞 在小肠中，转导糖刺激来引导糖的偏好。这一假设建立在最近的 观察：1)十二指肠上皮含有一群谷氨酸能神经足细胞，用 囊泡谷氨酸转运体1；2)迷走神经对十二指肠内糖刺激的反应依赖于 谷氨酸能信号；以及3)小鼠对糖而不是非卡路里甜味剂的偏好被以下因素消除 使一部分肠内分泌细胞沉默。本申请的目标有三个：1)确定 糖是如何激活谷氨酸能神经足细胞的；2)建立谷氨酸能肠道至迷走神经 糖激活的信号通路；以及3)确定谷氨酸能神经豆荚信号在 喜欢吃糖。本研究的结果可以为基于GUT的设计提供基础 通过靶向受体和信号来抑制食糖欲望的药物疗法 谷氨酸能上皮细胞的分子。

SUMMARY Despite the clear link between sugar overconsumption and metabolic syndrome, how the gut senses and communicates the presence of sugar to the brain remains unknown. Studies have shown that preference for sugars depends not on their sweet taste in the oral cavity, but rather on their entrance into the intestine. Therefore, understanding how the gut communicates information about ingested sugars could open a new path for pharmacotherapeutics for treating metabolic disease. The mechanisms of sensing nutrients in the gut are thought to involve the slower paracrine and endocrine action of peptides released from enteroendocrine cells. In recent years it has become evident that in addition to their canonical paracrine function, enteroendocrine cells also form synapses with nerves in the underlying intestinal and colonic mucosa. These gut epithelial cells that form synapses are known as neuropod cells. Our overall hypothesis is that glutamatergic neuropod cells in the small intestine transduce sugar stimuli to guide sugar preference. This hypothesis builds on recent observations: 1) the duodenal epithelium contains a population of glutamatergic neuropod cells labeled by the vesicular glutamate transporter 1; 2) vagal nerve firing in response to intraduodenal sugar stimuli depends on glutamatergic signaling; and 3) a mouse's preference for sugar over non-caloric sweetener is abolished by silencing a subset of enteroendocrine cells. The objectives in this application are three-fold: 1) to determine how glutamatergic neuropod cells are activated by sugar; 2) to establish the glutamatergic gut-to-vagus nerve signaling pathway activated by sugars; and 3) to determine the role of glutamatergic neuropod signaling on sugar preference. The outcomes of this research could serve as a foundation to design gut-based pharmacotherapies that seek to curb the desire to consume sugar by targeting the receptors and signaling molecules of glutamatergic epithelial cells.