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。项目摘要/摘要 部分原因是肥胖和糖尿病的全球发病率上升，分子机制 调节喂养行为引起了很多关注。但是，尽管我们的 了解食物摄入和代谢如何协调，对神经回路知之甚少 和基因喂养的基因。此外，如何信号来自代谢（补充能量）和 享乐（用于奖励）喂养电路已整合以调节食物摄入量，而食物的选择仍不清楚。 虽然从哺乳动物模型生物中学到了很多东西，但很少有参与喂养行为的基因 由于难以执行这些遗传筛选，因此已经确定了能量稳态 型号。因此，使用遗传上的模型生物（例如果蝇）为您提供了理想的策略 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测定法 果蝇中的行为，发现苍蝇配备了一种检测营养价值的机制 食物独立于味道。具体而言，不足食物的苍蝇更喜欢富含卡路里的糖而不是零卡路里 甜味剂。通过遗传和行为筛选，我确定了苍蝇所需的保守基因 做出代谢选择。该基因是候选果蝇钠 - 葡萄糖转运蛋白（DSGLT） 在苍蝇大脑中的一个小子集神经元中表达。我的假设是DSGLT通过 监测血液中的葡萄糖水平。确实，该基因在哺乳动物中表达的同源物 据认为，下丘脑在响应不断变化的葡萄糖水平方面发挥了积极作用 神经元的兴奋性，但它们在喂养中的作用尚不清楚。随着葡萄糖神经感测的缺陷 下丘脑已被证明在肥胖的发展中起作用，并有助于2型 糖尿病，更好地了解分子机制至关重要 糖（基础）喂养和代谢的基础化。在此提案中，我提出了一个集中的策略 表征蝇候选者在葡萄糖敏感性和行为中的功能。我会确定是否 DSGLT是一种葡萄糖传感器，及其如何赋予表达其神经元的葡萄糖性特性。我会 分析表达该基因的神经回路是否需要并且足以选择代谢 糖，以及这些神经元中的糖敏的动力学调节食物选择行为。最后，我会的 进行两个有针对性的遗传筛选：一个鉴定涉及糖（糖（ DSGLT神经元，另一个识别SGLT下游的神经肽和神经肽回路 介导效应机制的神经元最终调节食物的选择。这些研究将提供 洞察糖敏的分子机制及其在进食中的作用。他们还将提供 哺乳动物的研究人员将未来用作分子和神经化学标记的哺乳动物研究人员 糖敏，喂养和疾病的研究。