Characterization of the Fetal Primate Epigenome and Metabolome Under In Utero

点击翻译按钮获取中文摘要

Project Summary. Obesity causes substantial social, economic and health burdens. The rate of obesity is escalating disproportionately in children (infants to young adults). This rapid increase is unlikely to be due to environment or genetics alone. Accumulating evidence from our laboratory and others suggests that adult metabolic diseases originate in utero, and likely occur through the reprogramming of gene expression via epigenetic changes in chromatin structure (an altered "histone code"). Of interest, we have observed in a rodent transgenerational model of intrauterine growth restriction (IUGR) that a diet supplemented with essential nutrients, yet unaltered in its caloric content, prevents adult metabolic disease and is associated with abrogation of reprogrammed gene expression. However, although such established models in rodents demonstrate that fetal alterations in the histone code are involved in the persistence and conveyance of the altered postnatal phenotype, little is known about the effects of maternal diet and resultant obesity on primate fetal biology. We hypothesized that a high fat diet in non-human primates would induce changes in hepatic chromatin structure resulting in altered expression of fetal genes critical to the development of childhood and adult obesity. Based on our preliminary data, the focus of this proposal is to apply developed high throughput technology (comparative epigenomics and metabolomics) to decipher the primate epigenome and metabolome in the obese maternal environment and then measure the impact of supplementation on the differentially altered epigenome and resultant disease. The novel innovation and significance resides within its potential to provide (1) an expanded understanding of the mechanism through which a maternal high fat diet reprograms primate gene expression and (2) a simple intervention (essential nutrient supplementation with neither diet nor behavioral modification) with tremendous potential impact given the current obesity epidemic and the lack of efficacious therapeutics.