[Truncated] Developmental programming is now recognised as a key factor in the onset and progression of several adult-onset diseases including hypertension, diabetes, stroke and heart disease. Exposure to a poor environment early in life, including in utero, can increase an individual’s susceptibility to such diseases much later in life. Accordingly, developmental origins of health and disease (DOHaD) has emerged as an important new field of biomedical research in recent years. Animal models show that a variety of fetal insults, including undernutrition, placental insufficiency and glucocorticoid excess, can program adult-onset diseases. Interestingly, the adverse programming effects of different fetal insults are surprisingly consistent, with metabolic and cardiovascular dysfunction prevalent in a range of animal models. Despite this consistency, the underlying mechanisms that drive adult-onset pathologies remain obscure. This thesis tested the hypothesis that fetal glucocorticoid excess (a well-defined programming insult) programs disturbances in the circadian biology of adult offspring, specifically in relation to the expression of clock genes and their downstream targets in key metabolic tissues. Seven core clock genes (Bmal1, Clock, Per1, Per2, Per3, Cry1 and Cry2) form part of an intricate network that operates in both central (i.e. within the hypothalamus) and peripheral tissues (e.g. liver and adipose) to optimise cellular metabolism in relation to food and activity rhythms. This function of the clock network is mediated via transcriptional effects on a wide range of downstream gene targets. Importantly, previous research shows that disruption of clock gene networks results in metabolic disturbances, but whether these critical networks are influenced by developmental programming insults is unknown.
Latency is another important concept within the DOHaD field. Thus, certain developmental programming outcomes emerge in postnatal life only in a ‘challenged’ environment (e.g. overnutrition). Therefore, this thesis also tested the hypothesis that a high-fat diet exacerbates the adverse programming effects of fetal glucocorticoid excess, including disturbances in clock gene expression. Finally, in contrast to exacerbation by a postnatal challenge, adverse programming effects can also be attenuated by postnatal interventions, including hormonal treatments or dietary modifications. For example, our laboratory has previously shown that postnatal dietary supplementation with omega-3 fatty acids rescues many of the adverse outcomes otherwise programmed by fetal glucocorticoid excess. Therefore, the final aim of this thesis was to determine whether postnatal dietary supplementation with omega-3 fatty acids could alleviate glucocorticoid-programmed effects, including those in the circadian networks, even in the presence of a high-fat diet.
|Qualification||Doctor of Philosophy|
|Publication status||Unpublished - Nov 2014|