Neural and molecular mechanisms of glucosensation mediating food choice behavior

7.项目摘要/摘要 部分由于全球肥胖症和糖尿病发病率的上升，分子机制 规范喂食行为受到了人们的广泛关注。然而，尽管我们的 了解食物摄取和新陈代谢是如何协调的，对神经回路知之甚少 以及与进食有关的基因。此外，来自新陈代谢(补充能量)和 享乐(为了奖励)喂养回路被集成起来，以调节食物的摄入量和食物选择仍然不清楚。 虽然已经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很少 和能量动态平衡已经被确定，因为在这些生物中进行遗传筛选是困难的 模特们。因此，使用一种可遗传的模式生物，如果蝇，提供了一种理想的策略来 补充哺乳动物研究。在我攻读博士后期间，我开发了一种研究食物选择的方法 在果蝇中的行为，并发现果蝇配备了一种检测营养价值的机制 不受口味影响的食物。具体地说，缺乏食物的果蝇更喜欢高卡路里的糖，而不是零卡路里的 甜味剂。通过遗传和行为筛选，我确定了一种保守的基因，这是苍蝇 做出代谢性喂养选择。该基因是果蝇钠葡萄糖转运蛋白(DSGLT)的候选基因。 在苍蝇脑中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 监测血液中的血糖水平。事实上，这种基因的同源物在哺乳动物中表达 下丘脑被认为在对血糖水平变化的反应中发挥积极作用，通过影响 神经元的兴奋性，但它们在进食中的作用尚不清楚。作为葡萄糖神经感觉的缺陷， 下丘脑已被证明在肥胖症的发生和2型肥胖症的发生中起作用。 因此，进一步了解糖尿病的分子机制是至关重要的。 摄食和新陈代谢中的葡萄糖敏感作用。在这份提案中，我提出了一个有重点的战略，以 描述果蝇候选基因dSGLT在葡萄糖感觉和行为中的功能。我会决定是否 DSGLT是一种葡萄糖感受器，它是如何向表达它的神经元授予葡萄糖感受性的。这就做 分析表达该基因的神经回路对于代谢产物的选择是否必要和充分 糖，以及这些神经元中葡萄糖感觉的动态如何调节食物选择行为。最后，我会 进行两个有针对性的基因筛查：一个是识别葡萄糖感应下游涉及的其他基因 DSGLT神经元和另一种识别SGLT下游神经肽和神经肽回路的方法 负责调节最终调节食物选择的效应器机制的神经元。这些研究将提供 对葡萄糖感应的分子机制及其在摄食中的作用的洞察。他们还将提供 拥有保守基因的哺乳动物研究人员将在未来用作分子和神经化学标记 葡萄糖调节、摄食和疾病的研究。

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.