Roles for Glucosensors in Taste Function

葡萄糖传感器在味觉功能中的作用

• 批准号: 10296673
• 负责人: Lindsey A Schier
• 金额: $ 46.1万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10296673
• 关键词: Amino Acids; Apical; Artificial Sweeteners; Behavior; Behavioral; Beverages; Brain; CNS processing; Cells; Chronic; Consummatory Behavior; Consumption; Desire for food; Diabetes Mellitus; Diet; Dietary Intervention; Dietary Sugars; Discrimination; Electrophysiology (science); Enzyme Activation; Enzymes; Esthesia; Food; Fructose; G-Protein-Coupled Receptors; Genetic; Glossopharyngeal nerve structure; Glucokinase; Glucose; Goals; Human; Ingestion; Laboratories; Learning; Ligands; Link; Liquid substance; Measures; Metabolic; Modeling; Molecular; Motivation; Mus; Nerve; Nutrient; Obesity; Oral; Oral cavity; Outcome; Output; Palate; Pathway interactions; Peripheral; Pharmacology; Play; Property; Psychophysics; Publishing; Research; Rewards; Rodent; Role; Sensory; Series; Signal Transduction; Site; Taste Buds; Taste Perception; Testing; Tissues; Tongue; United States; Water; Work; afferent nerve; chorda tympani; detection of nutrient; dietary; experience; experimental study; glucose receptor; interdisciplinary approach; neurophysiology; neurotransmission; novel; nutrition; preventable death; receptor; relating to nervous system; response; sensory input; sensory mechanism; sugar; sweet receptor; sweet taste perception; taste system; transmission process

PROJECT SUMMARY Obesity and diabetes are associated with the chronic overconsumption of high sugar foods and fluids, driven in large part by their palatable taste. A single heterodimeric G-protein coupled receptor (T1R2+3) found in mammalian taste cells is widely considered the principal means through which all simple sugars are detected and promote ingestion via the gustatory system. Yet, recent studies from our laboratory revealed that rodents come to respond more positively to the orosensory properties of glucose over fructose, when provided the opportunity to learn about their divergent metabolic consequences, and this phenomenon does not require the canonical T1R2+3 taste receptor. Collectively, these published studies point to the existence of a previously unknown taste receptor linked to glucose appetite. The preliminary findings included in this proposal now show that glucokinase, a phosphorylating enzyme involved in other glucosensing mechanisms, is expressed in murine taste cells. We further demonstrate that glucokinase levels in the taste tissue are regulated by energy state and dietary sugar exposure. Moreover, pharmacological activation of lingual glucokinase specifically bolsters licking behavior and neural responsiveness in the chorda tympani nerve for glucose, but not fructose or water. Our working hypothesis is that glucokinase is part of a T1R2+3-independent taste receptor that transduces glucose- specific signals in the gustatory system. The overall goal of this proposal is to further clarify the functional and molecular properties of this novel gustatory glucosensor. In Aim 1, we will combine genetic and pharmacological approaches to selectively disrupt and/or activate canonical “sweet” taste inputs and lingual glucokinase while measuring taste-driven licking for various “sweet” and “non-sweet” tastants in sugar-naïve and sugar-exposed mice. With immunoblot and qPCR, we will further quantify changes in glucokinase and other sensory mechanisms linked to glucokinase in taste tissue as a function of dietary sugar exposure. In Aim 2, we will combine genetic and pharmacological approaches to psychophysically assess the discriminability of glucose, fructose, and other tastants in a series of two response operant discrimination tasks in order to fully elucidate the behavioral outputs functionally linked to gustatory glucosensors. In Aim 3, we will combine genetic and pharmacological approaches with electrophysiology to determine how T1R2+3-independent, glucokinase-linked taste signals are neurally-transmitted from tongue to brain. The outcomes of these aims will identify novel and potentially critical aspects of nutrient sensing, with the ultimate goal of identifying potential new strategies to curb appetite.

项目摘要 肥胖和糖尿病与高糖食物和液体的长期过度消费有关， 很大程度上取决于它们美味的味道。一个单一的异源二聚体G蛋白偶联受体（T1 R2 +3）发现于 哺乳动物的味觉细胞被广泛认为是检测所有单糖的主要手段 并通过味觉系统促进摄入。然而，我们实验室最近的研究表明， 来更积极地响应葡萄糖的orosensory属性超过果糖，当提供 有机会了解他们不同的代谢后果，这种现象并不需要 典型的T1 R2 +3味觉受体。总的来说，这些已发表的研究表明存在以前的 与葡萄糖食欲有关的未知味觉受体。该提案中的初步调查结果显示， 葡萄糖激酶是一种参与其他葡萄糖传感机制的磷酸化酶， 味觉细胞我们进一步证明了味觉组织中的葡萄糖激酶水平受能量状态的调节， 膳食糖暴露。此外，舌葡萄糖激酶的药理学激活特别支持舔 行为和鼓索神经对葡萄糖的神经反应性，而不是果糖或水。我们 工作假设是葡萄糖激酶是T1 R2 +3非依赖性味觉受体的一部分， 味觉系统中的特定信号。本提案的总体目标是进一步明确职能和 这种新型味觉葡萄糖传感器的分子特性。在目标1中，我们将联合收割机遗传学和药理学相结合 选择性破坏和/或激活典型“甜”味输入和舌葡糖激酶的方法， 测量未接触糖和暴露于糖中的各种“甜”和“非甜”促味剂的味觉驱动的舔 小鼠通过免疫印迹和qPCR，我们将进一步量化葡萄糖激酶和其他感觉神经元的变化。 与味觉组织中葡萄糖激酶相关的机制作为膳食糖暴露的函数。在目标2中，我们将 联合收割机结合遗传学和药理学方法，从精神病学角度评估葡萄糖的可辨别性， 果糖和其他促味剂在一系列的两个反应操作性辨别任务，以充分阐明 行为输出功能上与味觉葡萄糖传感器相关。在目标3中，我们将联合收割机结合遗传和 药理学方法与电生理学，以确定如何T1 R2 +3独立，葡萄糖激酶连接 味觉信号通过神经从舌头传递到大脑。这些目标的结果将确定新的和 营养感测的潜在关键方面，最终目标是确定潜在的新战略， 胃口