Role of Metabolic Sensing in Human Sweet Taste

 说明书(申请人提供)有压倒性的证据表明，甜味受体亚单位T1R2和T1R3对小鼠和人类的甜味感都是关键。尽管T1R受体对甜味很重要，但有证据表明，存在检测或调节甜味的替代途径。舌的味觉细胞与肠道和胰腺的味觉样内分泌细胞之间的共性使得“肠型”糖感受器(例如葡萄糖转运体(GLTS)和钠-葡萄糖共转运体(SGLTs))或“胰腺型”代谢感受器(三磷酸腺苷门控KATP通道)也可能存在于味觉细胞中，并在糖的甜感中发挥作用。这个项目的主要目标是识别和表征人类味觉感受器细胞用来感觉糖和卡路里的T1R非依赖性机制。我们假设糖转运体和代谢感受器是人类味觉感受器细胞T1R非依赖性糖感觉的基础。我们还假设，人类味觉细胞的代谢反应有助于感知甜味，并有助于传递对营养物质的更强偏好，而不是非热量的甜味剂。我们进一步假设，葡萄糖运输到对甜味反应敏感的人类味觉细胞的代谢会导致细胞内ATP升高，从而关闭味觉细胞的KATP通道，使细胞去极化。我们将通过在培养的人类味觉感受器细胞中进行组织学和功能研究来验证这些假设，并在人类受试者中进行味觉心理物理测试。总之，这些研究将确定糖转运体和KATP通道是否存在并活跃在人类味觉细胞中，以及它们是否可能对人类受试者的糖感和口服奖赏做出贡献。如果能够在不增加卡路里的情况下刺激甜味系统中的这种代谢感应器，它可能会提供一种有效的手段，帮助减少美国饮食中的过量糖，从而降低肥胖和其他与过度摄入卡路里相关的疾病的风险。

 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.