Mechanisms of glucosensation mediating food choice behavior in Drosophila

描述（由申请人提供）：部分由于全球肥胖和糖尿病发病率的上升，调节摄食行为的分子机制受到了广泛关注。然而，尽管我们对食物摄入和新陈代谢如何协调的理解有了极大的提高，但我们对进食背后的神经回路和基因知之甚少。此外，来自代谢（补充能量）和享乐（奖励）进食回路的信号如何整合以调节食物摄入和食物选择仍不清楚。虽然从哺乳动物模式生物中已经了解了很多，但由于在这些模型中进行遗传筛选的困难，很少有涉及摄食行为和能量稳态的基因被确定。因此，使用一种遗传上可适应的模式生物，如果蝇，为补充哺乳动物研究提供了一个理想的策略。在我的博士后研究期间，我开发了一个实验来研究果蝇的食物选择行为，并发现果蝇具有一种独立于味道来检测食物营养价值的机制。具体来说，缺乏食物的果蝇更喜欢富含卡路里的糖，而不是零卡路里的甜味剂。通过基因和行为筛选，我发现了一种保守的基因，这种基因是果蝇做出代谢进食选择所必需的。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通过监测血液中的葡萄糖水平来调节食物选择。事实上，在哺乳动物下丘脑中表达的这种基因的同源物被认为通过影响神经元的兴奋性，在对葡萄糖水平变化的反应中发挥积极作用，但它们在进食中的作用尚不清楚。由于下丘脑对葡萄糖的神经感知缺陷已被证明在肥胖的发生和2型糖尿病的发生中起作用，因此更好地了解糖感觉在摄食和代谢中的分子机制至关重要。在本提案中，我提出了一个重点策略来表征果蝇候选dSGLT在葡萄糖感觉和行为中的功能。我将确定dSGLT是否是葡萄糖传感器，以及它如何赋予表达它的神经元葡萄糖感应特性。我会分析表达这种基因的神经回路是否必要

DESCRIPTION (provided by applicant): 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.