Dietary induced predictive adapted responses causing metabolic syndrome

If a pregnant woman eats a healthy diet the developing baby would be expected to develop normally in most pregnancies. We suggest that providing the developing baby, child and then adult continues to eat a healthy diet throughout life, the risk of adult diabetes and heart disease will be low. We reason that in the womb the healthy diet allows the baby to develop a normal metabolism and that this baby¿s metabolism is primed to cope with a healthy diet also in childhood and adulthood. The risk of this person developing adult diabetes and heart disease later in life is very, very low. However if the baby is not brought up after birth and throughout childhood to eat a healthy diet, but eats instead a diet rich in fat, the baby¿s metabolism is now not able to cope with this diet, because in the womb it had never been exposed to these foods. We reason that this occurs because during development in the womb the baby was never exposed to unhealthy foods and therefore its metabolism did not develop to cope. When this child eats these unhealthy foods in childhood and then in adulthood because its metabolism has not developed to cope there is a marked increase in that person developing adult diabetes and heart disease. Therefore it is very important to study the effect of the combination of the pre-natal and the post-natal diets. We argue that where there is imbalance, or large differences, between these diets the effects on the offspring can be severe and risk of adult disease and heart disease later in life increases considerably. Only by choosing an animal model is it possible to study this phenomenon, because it is necessary to change both the pre- and post-natal diets and it would be unethical to undertake these changes in pregnant mothers and their babies. It is our intention of undertaking this study using a rodent model. Joint with BB/D001633/1.

This proposal aims to identify key molecular events underlying pre-natal induction of phenotypic susceptibility to metabolic syndrome. We will develop work published in which we examined the predictive adaptive response for liver lipid metabolism in the adult offspring after exposure to either pre-natal high fat and high protein, or pre-natal chow. This work showed programmed hepatic lipid metabolism in the offspring and has been the subject of a press release from the American Physiological Society. We will therefore establish an animal model wherein a nutritional mismatch between pre-natal and post-natal environments alters the adult phenotype of the offspring to resemble human metabolic syndrome. We are suggesting that the pre-natal maternal diet produces a predictive adaptive response in the developing offspring that sets metabolism. If these offspring are subsequently exposed to an unfavourable post-natal diet (ie. high fat, high protein), the offspring¿s metabolism is unable to respond appropriately and the inappropriate response renders the animal particularly susceptible to developing metabolic syndrome. To address our aim we will study blood pressure, adiposity, plasma lipids and plasma glucose. We will study lipid metabolism in liver, skeletal muscle and adipose tissues. We will examine small arteries from the mesenteric and femoral circulations and aorta at the time of killing of the adult offspring to study constrictor and dilator function in small vessels. We will also study potential mechanisms potentially involved in the pathogenesis of the metabolic syndrome including methylation status, mitochondrial DNA mutations and factors involved in appetite regulation in the adult offspring. Our proposed study will confirm or refute our testable hypothesis and provide the scientific basis for understanding how unbalanced diet in early life contributes to later metabolic syndrome which are of direct relevance to humans. This will lead to the design of intervention strategies to prevent such disease. The study is especially relevant as it forms part of an integrated research strategy in the applicants centre, comprising epidemiological studies (including those of dietary intervention before and during pregnancy), clinical physiology of subjects in our population cohorts, human development and genetics. Potential outcomes: this study will allow us to establish if changes in gene expression associated with the experimentally induced metabolic syndrome phenotypes are due to changes in the integrity of their mitochondrial DNA (mtDNA), and whether these changes in turn are due to alteration in methylation of the genes nuclear DNA. If such is the case then these may be a useful predictive marker for levels of tolerance and effectiveness of PARs to the development of metabolic syndrome. Joint with BB/D001633/1.