Transcriptional Regulation of Nutritional Homeostasis

营养稳态是一个基本的生物学过程，涉及调节摄食行为和消化后生理，以平衡食物摄入与能量消耗。为了维持营养平衡，大脑通过整合来自各种外周器官的输入来监测身体的能量状态。大脑产生适当的激素和神经元输出，导致营养吸收、储存或释放的变化，代谢率的变化和摄食行为的适应。神经肽和肽激素在这些器官间的通信中起着核心作用，并且中断可导致代谢紊乱，如肥胖和糖尿病。最近，研究表明，在组织之间发生的基因表达的协调变化，以响应肥胖症或糖尿病的条件和跨组织的相关表达的基因更有可能对它们之间交换的信息，而不是由特定于每个组织的调节事件驱动。许多控制哺乳动物体内营养平衡和行为的调节肽在果蝇中有同源物，并且具有类似的功能。此外，果蝇已被证明是非常有用的研究基因调控，因为它的遗传易处理性，完整的基因组序列的可用性和它的顺从性，许多功能基因组学技术。我们将利用果蝇作为模式生物的优势，确定通过器官间通讯调节营养稳态的神经肽和肽激素，并阐明确保组织间协调差异基因表达的分子机制。我们将对已知参与果蝇营养感测的三种内分泌组织进行转录组分析：大脑，肠道和脂肪体，来自不同饲养条件下饲养的果蝇。这种分析将产生一个全面的概述肽基因，改变他们的表达，以响应营养状况的变化。然后，我们将建立组织间共表达网络，以识别在不同组织中随着摄食条件的变化而表现出相关表达变化的基因。我们将从这些网络中提取肽基因，并分析其敲低和过表达对代谢参数（如葡萄糖，糖原和脂质含量）以及不同组织中相关基因表达的影响。这些实验将表明哪些肽参与营养稳态的器官间通信。最后，我们将利用我们之前在实验室开发的系统生物学工具阐明控制这些相关基因表达的基因调控网络的架构。该项目独特地结合了最先进的实验方法和计算生物学，以显着增加我们对控制组织间协调差异基因表达的转录机制的了解。因此，拟议的工作将对包括系统生物学、生理学和转录在内的几个生物学领域产生直接影响。鉴于代谢稳态失调可引起糖尿病和肥胖等疾病，这项工作也可能有助于我们了解这些病理学的分子机制。

Nutritional homeostasis is a basic biological process that involves adjusting feeding behaviour and post-digestive physiology to balance food intake with energy expenditure. In order to maintain nutritional homeostasis, the brain monitors the energy state of the body by integrating inputs from various peripheral organs. The brain generates appropriate hormonal and neuronal outputs resulting in changes in nutrient uptake, storage or release, in changes in metabolic rate and in adaptation of feeding behaviour. Neuropeptides and peptide hormones play a central role in these inter-organ communications and disruption can lead to metabolic disorders such as obesity and diabetes. Recently, studies have indicated that coordinated changes in gene expression occur between tissues in response to obesity or diabetic conditions and that genes with correlated expression across tissues are more likely to react to information exchanged between them rather than to be driven by regulatory events specific to each tissue. The actual mechanisms that drive coordinated gene expression between tissues remain unknown.Many regulatory peptides that control nutritional homeostasis and behaviour in mammals have a homolog in the fruit fly Drosophila melanogaster and serve similar functions. Furthermore, the fruit fly has proven to be extremely useful to study gene regulation because of its genetic tractability, the availability of the complete genome sequence and its amenability to many functional genomics techniques. We will take advantage of the strengths of Drosophila as a model organism to identify the neuropeptides and peptide hormones that regulate nutritional homeostasis through inter-organ communication and to elucidate the molecular mechanisms that ensure coordinated differential gene expression between tissues. We will perform transcriptome analysis on three endocrine tissues known to be involved in nutrient sensing in Drosophila: the brain, the gut and the fat body, from flies reared under different feeding conditions. This analysis will generate a comprehensive overview of the peptide genes that change their expression in response to changes in nutritional status. We will than establish tissue-to-tissue coexpression networks to identify genes that show correlated expression changes in response to changing feeding conditions across tissues. We will extract peptide genes from these networks and analyse the effect of their knock-down and overexpression on metabolic parameters such as glucose, glycogen and lipid content, and on the expression of correlated genes in different tissues. These experiments will indicate which peptides are involved in the inter-organ communication of nutritional homeostasis. Lastly, we will elucidate the architecture of the gene regulatory networks that control the expression of these correlated genes using systems biology tools that we previously developed in our lab.This project uniquely combines state-of-the-art experimental methodologies and computational biology to significantly increase our knowledge of the transcriptional mechanisms controlling coordinated differential gene expression between tissues. The proposed work will therefore have an immediate impact on several biological fields including systems biology, physiology and transcription. Given the fact that dysregulation of metabolic homeostasis can give rise to diseases such as diabetes and obesity, this work may also contribute to our understanding of the molecular mechanisms underlying these pathologies.