Integrating metabolic signals through FOXO transcriptional complexes.

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The FOXO transcription factors are a group of proteins that play a key role in balancing energy intake versus energy usage. Maintaining such metabolic balance has important health consequences particularly as we age. For example, being overweight or obese increases our susceptibility to multiple long-term diseases during ageing and can have a substantial impact on quality of life. Given the current global rise in obesity levels, this poses serious social and economic concerns to society. New ways to reduce the burden of ill health associated with poor metabolic outcomes are therefore urgently required.An important finding in the field is that very similar biological processes regulate the way in which animals across evolutionarily diverse species maintain metabolic balance in response to changes in the nutritional environment. We can therefore use simple laboratory models such as the fruit-fly, Drosophila melanogaster, to effectively study the processes that drive human metabolic disease. This approach has already been used to identify new drug targets to treat diseases associated with disruptions to metabolic regulation including some forms of cancer. The FOXO proteins function downstream of the highly conserved insulin/IGF-like signalling (IIS) pathway. This pathway functions in different animals, including humans, to coordinate and allocate nutrients taken in from the environment to different tissues and physiological processes. Preventing proper functioning of this pathway causes similar disruptions to metabolic physiology in Drosophila and humans. FOXO proteins perform their role by directly binding to target genes within the DNA of the cell to change their expression. Interestingly, our recent data shows that the expression of a group of these genes that code for proteins with important functions in regulating metabolism are influenced by FOXO activity even when FOXO is unable to bind to DNA. This suggests that FOXO is regulating the expression of these genes not by directly binding to the DNA itself but by binding to other proteins that are localised to the DNA. Our data suggests that these FOXO-protein interactions are important for relaying metabolic information within the cell. We do not yet fully understand the nature of these FOXO-protein interactions, but this knowledge is essential to understand the different roles of FOXO proteins in metabolic regulation. In this project, we will use Drosophila as a simple model to define how FOXO proteins relay key metabolic signals and maintain metabolic health without binding to DNA. We will identify and characterise all the proteins that bind to and localise FOXO to target genes. We already have candidate proteins to test and so we will examine in more detail the nature of these interactions using both biochemical and protein interaction assays in living cells. We will also manipulate the expression and activity of our candidate proteins within specific tissues to determine the downstream processes for which these interactions are important in maintaining metabolic health. Together, this knowledge will enable us to fully characterise the role of these clinically relevant transcriptional regulators in coordinating appropriate metabolic responses. Abberrant FOXO activity is linked to metabolic disease but treatments targeting FOXO directly are difficult to implement because it has many different functions. This project is an essential stage for the identification of new drug targets that could be used to treat many diseases that are pathologically linked to poor metabolic health thereby promoting human health and well-being across the lifecourse.