Neural and molecular mechanisms of glucosensation mediating food choice behavior

7.项目总结/摘要 部分由于肥胖和糖尿病的全球发病率上升， 调节摄食行为受到了广泛关注。然而，尽管我们的收入大幅增加， 虽然我们不了解食物摄入和新陈代谢是如何协调的，但我们对神经回路知之甚少。 和进食的基因。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和食物选择仍然不清楚。 虽然从哺乳动物模式生物中已经了解了很多，但很少有基因参与摄食行为 和能量稳态已经被确定，因为在这些疾病中进行基因筛选是困难的。 模型因此，使用遗传上顺从的模式生物如果蝇提供了一种理想的策略， 补充哺乳动物研究。在我的博士后研究期间，我开发了一种研究食物选择的方法， 行为，并发现苍蝇配备了一种机制，以检测营养价值的 食物独立于口味。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 甜味剂。通过遗传和行为筛选，我确定了一个保守的基因，这是苍蝇所必需的， 做出代谢性进食选择。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，在哺乳动物中表达的该基因的同源物 下丘脑被认为在响应葡萄糖水平的变化中起着积极的作用， 神经元的兴奋性，但其在喂养中的作用尚不清楚。由于葡萄糖神经感应缺陷， 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。 糖尿病，最重要的是要更好地了解分子机制， 葡萄糖感觉是摄食和代谢的基础。在这份提案中，我提出了一项重点战略， 表征果蝇候选dSGLT在葡萄糖感觉和行为中的功能。我会决定 dSGLT是一种葡萄糖传感器，以及它如何将葡萄糖传感特性赋予表达它的神经元。 分析表达该基因的神经回路是否是选择代谢的必要和充分的。 糖，以及这些神经元中葡萄糖感觉的动力学如何调节食物选择行为。最后要 进行两个靶向基因筛选：一个是鉴定参与葡萄糖传感下游的其他基因， dSGLT神经元和另一个用于鉴定SGLT下游的神经肽和神经肽回路 神经元介导效应器机制，最终调节食物选择。这些研究将提供 深入了解葡萄糖感觉的分子机制及其在进食中的作用。他们还将提供 哺乳动物研究人员与保守的基因作为分子和神经化学标记在未来使用 对葡萄糖感觉、进食和疾病的研究。

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.