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Transcriptional Regulation of Nutritional Homeostasis

Reference	BB/N00230X/1
Principal Investigator / Supervisor	Dr Korneel Hens
Co-Investigators / Co-Supervisors
Institution	University of Oxford
Department	Physiology Anatomy and Genetics
Funding type	Research
Value (£)	480,184
Status	Completed
Type	Research Grant
Start date	01/01/2016
End date	30/06/2019
Duration	42 months

Abstract

Inter-organ communication is essential to achieve energy homeostasis. Food intake needs to be balanced with energy expenditure by adjusting feeding behaviour and post-digestive physiology. Neuropeptides and peptide hormones play an important role in nutritional homeostasis. We aim to identify all neuropeptides and peptide hormones in the fruit fly Drosophila melanogaster that are involved in the regulation of metabolic homeostasis through inter-organ communication. We will first determine the neuropeptides and peptide hormones that are transcriptionally regulated in response to changes in nutritional status in three endocrine tissues known to be involved in metabolic homeostasis: the brain, the gut and the fat body. This will be achieved by performing RNA-seq on these tissues, dissected from adult flies reared under six different feeding conditions. To identify the peptides involved in inter-organ communication, we will start from the observation that tissue-to-tissue coexpression networks highlight communication between tissues. Modules within these networks consist of genes whose expression profiles are highly correlated across tissues. We will mine these modules for nutritionally regulated peptide genes and evaluate the effect of their knock-down or overexpression on nutrient levels and on the expression of nutritionally regulated peptides in other endocrine tissues. Lastly, we will map the gene regulatory networks that ensure the coordinated differential gene expression between tissues using a high-throughput yeast one-hybrid system and microfluidics techniques, allowing us for the first time to map the regulatory hierarchy that governs gene co-expression across tissues.

Summary

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.

Impact Summary

Insecticide resistance has become a serious problem in controlling insect pests. Failure to control pest insects may lead to significant crop losses. Furthermore, vector-borne diseases such as malaria account for more than 17% of all infectious diseases, causing more than 1 million deaths annually. The development of insecticide resistance and the environmental impact of chemical insecticides necessitate a new approach that is aimed toward the development of novel families of non-toxic, insect-specific compounds compatible with integrated pest management. This study will uncover neuropeptides and peptide hormones that regulate nutritional homeostasis in the fruit fly. Antagonists of these peptides are prime candidates for such insect-specific compounds as they can potentially alter the metabolic state and feeding behaviour of insects. Furthermore, Drosophila is an excellent model organism to study the molecular action of such antagonists as many G protein-coupled receptors through which neuropeptides work, have been characterized. Although this is a basic science proposal, the pharmaceutical industry is likely to be interested in the research for its long term potential to help understand the transcriptional regulation of metabolic disorders such as obesity and diabetes. According to the World Health Organisation, approximately 60 million people have diabetes in the European region and the number of adults with diabetes has more than doubled over nearly three decades. Gaining a better knowledge of the molecular mechanisms underlying this disease is critical to develop novel treatments for a pathology that is rapidly becoming the most threatening epidemic of the 21st century. Specifically, this project will uncover the gene regulatory networks that govern the modulation of gene expression upon dietary changes and will identify the key transcription factors within these networks. The importance of transcriptional regulation in metabolic homeostasis is evidenced by the occurrence of major metabolic disorders when transcription factor function is perturbed. Five out of six genes causing maturity-onset diabetes of the young (MODY), are transcription factors. The therapeutic use of high-affinity ligands of the transcription factor nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) in patients with diabetes mellitus and metabolic syndrome illustrates the potential of transcription factor as drug targets. The proposed research involves the use of several cutting-edge technologies, including robotics and microfluidics that are currently only available in a few labs in the world but that will become standard technologies in the near future. Our research staff will receive training in these technologies which will prepare them for highly skilled employment in the private and public sectors. Furthermore, by opening up these platforms to the research community at large we will generate a fertile ground for collaboration and discussion which will drive further technological advances. Ten percent of the children in the UK aged 10-11 are obese. It is critical that children are made aware of the importance of a healthy diet and the effects of obesity on health. We plan several outreach activities for school children where they can use the fruit fly to study the effect of dietary composition on food preference, circulating sugar levels, body weight and longevity. The fruit fly is an ideal model for this purpose as the results can be readily observed in a short time.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	Diet and Health, Neuroscience and Behaviour
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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