[Truncated abstract] Increased incidence of hypertension, insulin resistance, obesity and dyslipidemia, collectively referred to as the metabolic syndrome, has been linked to low birth weight, an indicator of a poor fetal environment. This association reflects developmental programming, a process by which organ systems are affected during early development such that disease states are more likely to emerge in adult life. Fetal glucocorticoid overexposure is thought to be a key factor that mediates developmental programming. Accordingly, maternal treatment with the synthetic glucocorticoid dexamethasone retards fetal growth and leads to delayed puberty, hypertension, hyperinsulinemia, and hyperleptinemia, either with or without increased adiposity, in adult offspring. Importantly, the postnatal environment can either amplify or attenuate the long-term outcome of developmental programming. The focus of this thesis was whether adverse developmental programming outcomes can be attenuated by the postnatal environment and thus provide therapeutic potential. Specifically, the effects of a postnatal diet rich in omega-3 fatty acids on glucocorticoid-induced developmental programming outcomes was investigated. ... The adipocyte phenotype was examined in Study 6, with hyperleptinaemia evident in offspring at 6 and 12 months of age in dexamethasone-exposed animals on a standard omega-3 diet, but this effect was prevented by a high omega-3 diet. The pattern of plasma leptin was paralleled by changes in leptin mRNA in retroperitoneal fat. Similarly, plasma levels of the inflammatory markers IL-6 and IL-1β were upregulated by prenatal glucocorticoid exposure and these were attenuated by postnatal dietary omega-3 fatty acids. Overall, omega-3 ingestion reduced adiposity, as indicated by measures of body composition. In conclusion, the studies presented in this thesis demonstrate for the first time that many of the detrimental effects of excess glucocorticoid exposure in utero on the adult phenotype can be attenuated by a postnatal diet rich in omega-3 fatty acids. This beneficial effect of omega-3 fatty acids was associated with a reversal of some (e.g. adiposal leptin) but not all (e.g. renal GR) 'programmed' changes in gene expression. These findings raise the possibility that dietary supplementation with omega-3 fatty acids may provide a viable therapeutic option for preventing and/or reducing adverse programming outcomes in humans.
|Qualification||Doctor of Philosophy|
|Publication status||Unpublished - 2006|