Roles for Glucosensors in Taste Function

葡萄糖传感器在味觉功能中的作用

• 批准号: 10514618
• 负责人: Lindsey A Schier
• 金额: $ 44.14万
• 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/10514618
• 关键词: Amino Acids; 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; Pathway interactions; Peripheral; Phosphorylation; Play; Property; Psychophysics; Publishing; Research; Rewards; Rodent; Role; Sensory; Series; Signal Transduction; Site; Synaptic Transmission; Taste Buds; Taste Perception; Testing; Tissues; Tongue; United States; Water; Western Blotting; Work; afferent nerve; chorda tympani; detection of nutrient; dietary; experience; experimental study; glucose receptor; interdisciplinary approach; neural; neurophysiology; neurotransmission; novel; nutrition; pharmacologic; preventable death; receptor; 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.

项目概要 肥胖和糖尿病与长期过量摄入高糖食物和液体有关， 很大程度上是由于其美味的味道。 哺乳动物味觉细胞被广泛认为是检测所有单糖的主要手段 然而，我们实验室最近的研究表明，啮齿类动物会通过味觉系统促进摄入。 当提供以下条件时，对葡萄糖的口腔感觉特性的反应比果糖更积极 有机会了解它们不同的代谢后果，并且这种现象不需要 总的来说，这些已发表的研究表明先前存在一种典型的 T1R2+3 味觉受体。 该提案中包含的初步研究结果显示，未知的味觉受体与葡萄糖食欲有关。 葡萄糖激酶是一种参与其他葡萄糖生成机制的磷酸化酶，在小鼠中表达 我们进一步证明组织味觉中的葡萄糖激酶水平受能量状态和 此外，舌葡萄糖激酶的药理学激活特别会促进舔食。 鼓索神经对葡萄糖的行为和神经反应，但对果糖或水没有影响。 工作假设是葡萄糖激酶是 T1R2+3 独立味觉受体的一部分，可转导葡萄糖- 该提案的总体目标是进一步阐明味觉系统的功能和信号。 在目标 1 中，我们将结合遗传和药理学研究这种新型味觉葡萄糖传感器的分子特性。 选择性破坏和/或激活典型的“甜味”味觉输入和舌葡萄糖激酶的方法，同时 测量未接触糖和接触糖的各种“甜”和“非甜”促味剂的味觉驱动舔​​舐行为 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的变化。 在目标 2 中，我们将研究味觉组织中葡萄糖激酶与膳食糖暴露相关的机制。 结合遗传和药理学方法从心理物理学角度评估葡萄糖的辨别能力， 果糖和其他促味剂在一系列两种反应操作辨别任务中，以充分阐明 在目标 3 中，我们将把行为输出与味觉葡萄糖传感器结合起来。 使用电生理学的药理学方法来确定 T1R2+3 独立的葡萄糖激酶如何连接 味觉信号通过神经从舌头传递到大脑。 营养物传感的潜在关键方面，最终目标是确定潜在的新策略来遏制 食欲。