Functional characterization of endocrine taste cells

在过去的几年里，我的实验室探索了味觉信号元件在胃肠道(GI)化学感觉中的参与。特别是，肠腔中的大量营养素是如何被感知的，并反过来调节肠道特定的肠内分泌细胞的激素释放。我们已经确定，作为味觉检测/转导基础的非常相同的信号元件也在特定类型的肠道内分泌细胞，即所谓的肠道味觉细胞中表达。此外，这些信号蛋白在肠道细胞中发挥作用，有效地感觉肠道管腔内的饮食内容。这些肠道内分泌细胞的化学感觉反应包括释放激素以促进肠道的消化和代谢功能。味觉信号元件对胃肠道化学感觉的重要性的一个显著例子是观察到，1-Gustducin基因敲除小鼠在向肠腔注入葡萄糖时，不会从其肠道内分泌细胞分泌GLP-1(胰高血糖素样多肽1)-由于这一缺陷，这些小鼠的血浆胰岛素和血糖水平调节失调，导致它们处于糖尿病前期状态。最近，我们观察到一些激素和信号元件通常存在于肠道的内分泌细胞中，也存在于味觉细胞的子集中，我们称之为舌内分泌细胞或内分泌味觉细胞。我们假设，这些味觉细胞对味觉做出反应，会释放GLP-1和其他与味觉、消化和饱腹感相关的局部(旁分泌)和/或全身性影响的激素。此外，我们假设由Gustducin、T1R3、Trpm5等味觉转导元件介导的味觉信号在这些舌内分泌细胞的内分泌和旁分泌反应中起重要作用。我们的初步数据表明，GLP-1、胰高血糖素和PYY(肽YY)在内分泌味觉细胞中表达。此外，我们还发现，葡萄糖和甜味剂可以刺激这些味觉细胞释放GLP-1。这里提出的实验旨在进一步表征这些舌内分泌细胞的功能。我们结合分子、细胞、转基因、生理学和药理学的方法来确定：1.哪些肠道信号分子在舌内分泌细胞中表达；2.这些内分泌味觉细胞释放哪些激素响应特定的味觉；3.哪些味觉信号元件参与了味觉诱导的内分泌细胞释放激素的作用；4.内分泌味觉细胞释放的激素有什么局部或全身作用。这种多学科的方法有望为头位相反应的本质提供重要的新见解，调节味觉细胞释放GLP-1和其他激素来调节肠道功能。这项建议与食欲、饱腹感、糖尿病和肥胖症有医学上的相关性。作为味觉检测/转导基础的相同信号元件也在肠道内分泌细胞中表达，在那里它们的功能是感知肠道管腔内的饮食内容。许多激素通常存在于肠道的内分泌细胞中，也存在于味觉细胞的子集中，称为舌质内分泌细胞或内分泌味觉细胞。这些实验旨在鉴定和确定这些舌内分泌细胞的功能特征，这些细胞与食欲、饱腹感、糖尿病和肥胖症有医学上的相关性。

During the past few years my laboratory has explored the involvement of taste signaling elements in gastrointestinal (GI) chemosensation. In particular, how macronutrients in the gut lumen are sensed and in turn regulate hormone release from specific enteroendocrine cells of the gut. We have determined that the very same signaling elements that underlie taste detection/transduction also are expressed in specific subtypes of enteroendocrine cells, so-called taste cells of the gut. Moreover, these signaling proteins function in the gut cells to sense, in effect to taste, the dietary contents within the lumen of the gut. Chemosensory responses of these enteroendocrine cells include hormone release to promote the gut's digestive and metabolic functions. A striking example of the importance of taste signaling elements to GI chemosensation comes from the observation that 1-gustducin knockout mice do not secrete GLP-1 (Glucagon-Like Peptide 1) from their enteroendocrine cells in response to infusion of glucose into the gut lumen - because of this defect these mice have dysfunctional regulation of their plasma insulin and glucose levels, leading them to a prediabetic condition. Quite recently we have observed that a number of hormones and signaling elements typically found in enteroendocrine cells of the gut are present also in a subset of taste cells, which we're calling lingual endocrine cells or endocrine taste cells. We hypothesize that in response to tastants these taste cells release GLP-1 and other hormones that have local (paracrine) and/or systemic effects relevant to taste, digestion and satiety. Further, we hypothesize that taste signaling mediated by gustducin, T1R3, Trpm5 and other taste transduction elements contributes importantly to the endocrine and paracrine responses of these lingual endocrine cells. Our preliminary data show that GLP-1, glucagon and PYY (peptide YY) are expressed in endocrine taste cells. In addition, we have found that glucose and sweeteners elicit release of GLP-1 from these taste cells. The experiments proposed here aim to further characterize the functions of these lingual endocrine cells. We have combined molecular, cellular, transgenic, physiological and pharmacological methods to determine: 1. which gut signaling molecules are expressed in lingual endocrine cells; 2. which hormones are released from these endocrine taste cells in response to specific tastants; 3. which taste signaling elements are involved in tastant- elicited hormone release from endocrine taste cells; and 4. what are the local or systemic effects of endocrine taste cell-released hormones. This multidisciplinary approach has promise for providing significant new insights into the nature of cephalic phase responses regulating taste cell release of GLP-1 and other hormones to regulate gut functions. This proposal has medical relevance to appetite, satiety, diabetes and obesity. The same signaling elements that underlie taste detection/transduction also are expressed in gut enteroendocrine cells, where they function to sense the dietary contents within the lumen of the gut. A number of hormones typically found in enteroendocrine cells of the gut are present also in a subset of taste cells, called lingual endocrine cells or endocrine taste cells. The experiments proposed to identify and functionally characterize these lingual endocrine cells have medical relevance to appetite, satiety, diabetes and obesity.