Role of Metabolic Sensing in Human Sweet Taste

 说明（申请人提供）有压倒性的证据表明，甜味受体亚单位T1 R2和T1 R3是小鼠以及人类甜味感觉的关键。尽管T1 R受体对甜味具有明显的重要性，但有证据表明存在用于检测或调节甜味的替代途径。舌头的味觉细胞与肠道和胰腺的味觉样内分泌细胞之间的共同点使得“胰腺型”糖传感器（例如，葡萄糖转运蛋白（GLUT）和钠-葡萄糖共转运蛋白（SGLT））或“胰腺型”代谢传感器（ATP门控KATP通道）也可能存在于味觉细胞中并在糖的甜味感觉中起作用。该项目的主要目标是识别和表征人类味觉受体细胞用于感知糖和卡路里的T1 R独立机制。我们假设糖转运蛋白和代谢传感器的基础T1 R-独立的糖在人类味觉感受器细胞的传感。我们还假设，人类味觉细胞的代谢反应有助于甜味的感知，并有助于赋予对营养性甜味剂的更强偏好。我们进一步假设，转运到对甜味敏感的人类味觉细胞中的葡萄糖代谢导致细胞内ATP升高，从而关闭味觉细胞的KATP通道，使细胞去极化。我们将使用培养的人类味觉感受器细胞的组织学和功能研究以及人类受试者的味觉心理物理测试来验证这些假设。这些研究将共同确定糖转运蛋白和KATP通道是否存在于人类味觉细胞中并具有活性，以及它们是否可能有助于人类受试者的糖感知和口服奖励。如果甜味系统中的这种代谢传感器可以在不增加卡路里的情况下被刺激，它可以提供一种有效的手段来帮助减少美国饮食中过量的糖，从而降低肥胖和其他与卡路里过度消耗相关的疾病的风险。

 DESCRIPTION (provided by applicant) There is overwhelming evidence that the sweet receptor subunits T1R2 and T1R3 are key to the sense of sweet taste in mice, as well as in humans. Despite the clear importance of T1R receptors to sweet taste, there is evidence that alternative pathways exist for detection or modulation of sweet taste. Commonalities among taste cells of tongue and taste-like endocrine cells of gut and pancreas make it plausible that "intestinal-type" sugar sensors (e.g., glucose transporters (GLUTs) and sodium-glucose co-transporters (SGLTs)) or "pancreatic-type" metabolic sensors (ATP-gated KATP channels) might also be present in taste cells and function in sweet sensation of sugars. The main goal of this project is to identify and characterize T1R- independent mechanisms used by human taste receptor cells to sense sugars and calories. We hypothesize that sugar transporters and metabolic sensors underlie T1R-independent sugar sensing in human taste receptor cells. We also hypothesize that metabolic responses of human taste cells contribute to the perception of sweet taste and help impart the stronger preference for nutritive over non-caloric sweeteners. We hypothesize further that metabolism of glucose transported into sweet-responsive human taste cells leads to elevated intracellular ATP that closes the taste cell's KATP channels, depolarizing the cell. We will test these hypotheses using histological and functional studies in cultured human taste receptor cells and taste psychophysical tests in human subjects. Together these studies will determine if sugar transporters and KATP channels are present and active in human taste cells and if they are likely to contribute to sugar sensing and oral reward in human subjects. If this metabolic sensor in the sweet taste system can be stimulated without adding calories, it could provide an effective means to help reduce excess sugar in the US diet, thereby reducing the risk of obesity and other diseases associated with overconsumption of calories.