Transcriptional Regulation of Nutritional Homeostasis

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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.