119 Randel Lectureship: The Role of Maternal Nutrition in Developmental Programming Using a Sheep Model

Abstract Appropriate nutrition during gestation is critical for optimal fetal development and life-long health. Poor nutrition during gestation, defined as excess or restricted nutrition, can lead to altered growth and metabolic dysregulation in the offspring. Using a sheep model, we have demonstrated that both restricted- and over-feeding alter offspring growth, impair muscle growth, increase fat accumulation, alter circulating growth and metabolic hormones, and alter mRNA expression of genes involved in myogenesis, lipogenesis, inflammation, and glycogen metabolism. More importantly, these negative impacts of poor maternal nutrition persist through adulthood, and can be passed to subsequent generations. Using omics approaches, we have begun to elucidate the mechanisms by which maternal diet impacts developmental programming and contributes to these persistent effects. In offspring from restricted-fed mothers, fetal liver and muscle morphology demonstrated impaired growth and alterations in key metabolites in methionine, betaine, and bile salt pathways. In offspring from both restricted- and over-fed mothers, global metabolomics demonstrated altered lipid and protein metabolism profiles. These changes in metabolites likely contribute to maternal programming of offspring growth and metabolism including efficiency of energy utilization. In addition to changes in key genes involved in growth, lipid accretion, and protein synthesis, preliminary studies suggest these persistent effects may be due to changes epigenetic regulation in offspring. Using the sheep model of both restricted- and over-feeding we, and others, have demonstrated that the negative effects of poor maternal nutrition affect multiple key metabolic tissues during fetal development and that these changes persist into maturity. Therefore, the focus of our current studies is to determine the multigenerational impacts of poor maternal nutrition on offspring growth and health and elucidate the mechanisms that contribute to these persistent changes.