Neural and molecular mechanisms of glucosensation mediating food choice behavior

葡萄糖酸化介导食物选择行为的神经和分子机制

• 批准号: 9068114
• 负责人: Monica Dus
• 金额: $ 24.54万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9068114
• 关键词: Address; Affect; Animal Model; Animals; Architecture; Attention; Behavior; Behavioral; Behavioral Genetics; Biological Assay; Blood; Blood Glucose; Brain; Candidate Disease Gene; Cations; Cells; Choice Behavior; Complement; Defect; Development; Diabetes Mellitus; Disease; Dopamine Receptor; Drosophila genus; Eating; Electrophysiology (science); Esthesia; Feeding behaviors; Food; Food deprivation (experimental); Future; GABA Receptor; Genes; Genetic; Genetic Screening; Glucose; Glucose Transporter; Goals; Hemolymph; Homeostasis; Homologous Gene; Hypothalamic structure; Image; Imaging Device; In Vitro; Incidence; Kinetics; Knowledge; Label; Lead; Learning; Mammals; Measures; Mediating; Mentors; Metabolic; Metabolic Diseases; Metabolism; Modeling; Molecular; Monitor; Mutate; Neural Pathways; Neurons; Neuropeptide Gene; Neuropeptides; Neurotransmitters; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Obesity; Organ; Pathway interactions; Peptides; Peripheral; Phase; Physiological; Physiology; Play; Population; Process; Property; Regulation; Research; Research Personnel; Rewards; Role; Signal Transduction; Sleep Wake Cycle; Slice; Sodium; Starvation; Structure; Sweetening Agents; Taste Perception; Testing; Work; Xenopus oocyte; behavioral study; calcium indicator; cell type; extracellular; feeding; fly; gamma-Aminobutyric Acid; gene function; glucose monitor; glucose sensor; hedonic; in vivo; insight; knock-down; neural circuit; neurochemistry; preference; relating to nervous system; research study; response; sugar; targeted treatment; tool

7. PROJECT SUMMARY/ABSTRACT Due in part to the rise in the worldwide incidence of obesity and diabetes, the molecular mechanisms regulating feeding behavior have received much attention. However, despite the tremendous increases in our understanding of how food intake and metabolism are coordinated, very little is known about the neural circuits and genes underlying feeding. Furthermore, how signals from both metabolic (to replenish energy) and hedonic (for reward) feeding circuits are integrated to regulate food intake and food choice remain unclear. While much has been learned from mammalian model organisms, very few genes involved in feeding behavior and energy homeostasis have been identified because of the difficulty in performing genetic screens in these models. Thus, using a genetically amenable model organism such as the fruit fly provides an ideal strategy to complement mammalian research. During my postdoctoral studies I developed an assay to study food choice behavior in Drosophila and found that flies are equipped with a mechanism to detect the nutritional value of food independently of taste. Specifically, food-deprived flies prefer calorie-rich sugars to zero-calorie sweeteners. Through genetic and behavioral screens, I identified a conserved gene that is required for flies to make metabolic feeding choices. This gene, a candidate Drosophila Sodium-Glucose-Transporter (dSGLT) is expressed in a small subset neurons in the fly brain. My hypothesis is that dSGLT regulates food choice by monitoring glucose levels in the blood. Indeed, homologues of this gene expressed in the mammalian hypothalamus are thought to play an active role in responding to changing glucose levels by affecting the excitability of neurons, but their role in feeding is not known. As defects in neural sensing of glucose in the hypothalamus have been shown to play a role in the development of obesity and contribute to type-2 diabetes, it is of the utmost importance to better understand the molecular mechanism of glucosensation underlying feeding and metabolism. In this proposal I present a focused strategy to characterize the function of the fly candidate dSGLT in glucose-sensation and behavior. I will determine if dSGLT is a glucose sensor and how it confers glucosensing properties to the neurons that express it. I will analyze if the neural circuit expressing this gene is necessary and sufficient for the choice for metabolizable sugars, and how the dynamics of glucosensation in these neurons modulate food choice behavior. Finally, I will conduct two targeted genetic screens: one to identify other genes involved downstream of glucosensing in dSGLT neurons and the other to identify the neuropeptides and neuropeptide circuits downstream of SGLT neurons that mediate the effector mechanisms ultimately regulating food choice. These studies will provide insights into the molecular mechanisms of glucosensation and its role in feeding. They will also provide mammalian researchers with conserved genes to use as molecular and neurochemical markers in future studies of glucosensation, feeding, and disease.

7. 项目概要/摘要 部分由于全球肥胖和糖尿病发病率的上升，分子机制 调节喂养行为受到广泛关注。然而，尽管我们的 了解食物摄入和新陈代谢如何协调，但对神经回路知之甚少 和喂养背后的基因。此外，来自代谢（补充能量）和 享乐（奖励）喂养回路被整合以调节食物摄入量，但食物选择仍不清楚。 虽然我们从哺乳动物模式生物中学到了很多东西，但参与摄食行为的基因却很少 由于在这些疾病中进行基因筛选很困难，能量稳态已被确定。 模型。因此，使用遗传上适合的模型生物（例如果蝇）提供了一种理想的策略 补充哺乳动物研究。在博士后研究期间，我开发了一种研究食物选择的方法 果蝇的行为，发现苍蝇配备了一种机制来检测果蝇的营养价值 食物与味道无关。具体来说，食物匮乏的苍蝇更喜欢高热量的糖而不是零热量的糖 甜味剂。通过遗传和行为筛选，我发现了果蝇所需的保守基因 做出代谢喂养选择。该基因是果蝇钠葡萄糖转运蛋白 (dSGLT) 的候选基因 在果蝇大脑的一小部分神经元中表达。我的假设是 dSGLT 通过以下方式调节食物选择 监测血液中的葡萄糖水平。事实上，该基因的同源物在哺乳动物中表达 下丘脑被认为通过影响血糖水平在响应血糖水平变化方面发挥积极作用。 神经元的兴奋性，但它们在进食中的作用尚不清楚。由于葡萄糖的神经感觉缺陷 下丘脑已被证明在肥胖的发生中发挥作用并有助于 2 型肥胖 深入了解糖尿病的分子机制至关重要 进食和新陈代谢背后的葡萄糖酸化。在本提案中，我提出了一项重点战略 描述果蝇候选 dSGLT 在葡萄糖感觉和行为中的功能。我会确定是否 dSGLT 是一种葡萄糖传感器，以及它如何向表达它的神经元赋予葡萄糖传感特性。我会 分析表达该基因的神经回路对于选择可代谢的基因是否是必要和充分的 糖，以及这些神经元中葡萄糖的动态如何调节食物选择行为。最后，我会 进行两项有针对性的遗传筛选：一项是为了识别参与葡萄糖代谢下游的其他基因 dSGLT 神经元和其他神经元来识别 SGLT 下游的神经肽和神经肽回路 介导最终调节食物选择的效应机制的神经元。这些研究将提供 深入了解葡萄糖酸化的分子机制及其在喂养中的作用。他们还将提供 具有保守基因的哺乳动物研究人员未来可用作分子和神经化学标记 葡萄糖酸化、喂养和疾病的研究。