Transcriptional Regulation of Nutritional Homeostasis

营养动态平衡是一种基本的生物过程，它涉及调整摄食行为和消化后生理，以平衡食物摄入量和能量消耗。为了维持营养平衡，大脑通过整合来自不同外周器官的输入来监控身体的能量状态。大脑产生适当的荷尔蒙和神经元输出，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。神经肽和多肽激素在这些器官间的交流中发挥着核心作用，而干扰可能会导致代谢紊乱，如肥胖和糖尿病。最近，研究表明，组织间的基因表达发生了协调变化，以响应肥胖或糖尿病的情况，并且跨组织相关表达的基因更有可能对它们之间的信息交换做出反应，而不是受到每个组织特有的调控事件的驱动。驱动组织之间协调基因表达的实际机制尚不清楚。许多控制哺乳动物营养动态平衡和行为的调节肽在果蝇黑腹果蝇中具有同源性，并具有相似的功能。此外，果蝇已被证明是非常有用的研究基因调控，因为它的遗传易操纵性，可获得完整的基因组序列，它适合于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，鉴定通过器官间沟通调节营养动态平衡的神经肽和肽激素，并阐明确保组织之间协调差异基因表达的分子机制。我们将对果蝇在不同饲养条件下饲养的大脑、肠道和脂肪体这三个已知参与营养感知的内分泌组织进行转录组分析。这项分析将全面概述随着营养状态的变化而改变表达的多肽基因。然后，我们将建立组织到组织的共表达网络，以确定随着组织间摄食条件的变化而显示相关表达变化的基因。我们将从这些网络中提取多肽基因，并分析它们的下调和过度表达对葡萄糖、糖原和脂肪含量等代谢参数的影响，以及对不同组织中相关基因表达的影响。这些实验将表明哪些多肽参与了营养稳态的器官间通讯。最后，我们将使用我们之前在实验室开发的系统生物学工具来阐明控制这些相关基因表达的基因调控网络的架构。这个项目独特地结合了最先进的实验方法和计算生物学，显著增加了我们对控制组织之间协调差异基因表达的转录机制的知识。因此，拟议的工作将对系统生物学、生理学和转录等几个生物学领域产生立竿见影的影响。鉴于代谢平衡失调会导致糖尿病和肥胖症等疾病，这项工作也可能有助于我们理解这些病理基础的分子机制。

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.