Regulation of protein synthesis as a mechanism of nutritional programming and developmental origins of optimal health

The diet of an individual can have important health consequences at any stage of life. However there is evidence to suggest that the diet of women during pregnancy and while breastfeeding is particularly important as it has major long-term implications for the health of her baby. It has been shown that individuals with a low birth weight are not only less likely to survive delivery but are also at substantially increased risk of developing type 2 diabetes, high blood pressure and heart disease in adulthood and are more likely to die at a younger age. The underlying causes of the relationship between early growth and adult disease are not known, but it is thought that the quality of the diet of women during pregnancy and breastfeeding is critically important. Studies in animal models can be very useful in helping to decipher mechanisms of human diseases. We have shown that if pregnant and lactating rats have too little protein in their diet their offspring are small at birth and later develop diabetes. We have studied fat tissue and have identified key proteins that are much less abundant both in young men who had a low birth weight and in offspring of protein restricted rat mothers. The central dogma of biology is that the genetic material DNA is copied to an intermediary molecule RNA that is then translated into proteins. Our recent results suggest that the second step of this process is permanently altered (or 'programmed') in the offspring of animals or humans that had a sub-optimal diet. In our project we will study RNA from rat and human fat cells to identify new genes that are programmed to be expressed at different levels as a result of poor early life nutrition. We will also determine why it is that their RNA is not translated properly to make the corresponding proteins. Understanding these processes will enable us to identify individuals at risk and to develop intervention strategies to improve the health of pregnant and breast-feeding women and their offspring.

Fetal and early life nutrition has long-term (ie programmed) consequences for health. This has been termed the Developmental Origins of Health and Disease. Despite numerous studies confirming the concept of nutritional programming and its associations with long term health, the molecular mechanisms by which a phenomenon that occurs in utero or during very early life has phenotypic consequences many years later are poorly understood. This proposal addresses the fundamental underlying molecular mechanisms of nutritional programming. We hypothesise that programmed responses to sub-optimal nutrition in early life are significantly mediated by regulation of gene expression at a post-transcriptional level. We further hypothesise that diet-induced changes in regulatory factors such as miRNAs alter cellular memory and consequently impact on long term health of the organism. We will adopt an integrated approach to test these hypotheses, combining whole body nutritional programming, functional genomics and transcriptomics using both the well established maternal low protein rat model and human biopsy material. This will include both genome-wide and gene-specific analysis of adipose tissue. Understanding the mechanisms involved in nutritional programming could ultimately lead to diagnosis, prevention and treatment of the long term effects of diet on health.