Obesity prevalence in the US and other developed countries has increased dramatically in recent decades. This trend is affecting individuals at every age, including women of child- bearing age. A major concern is that maternal obesity during pregnancy may alter the intrauterine environmental and thereby perpetuate obesity in her offspring. The viable yellow agouti (Avy) mouse is an ideal model in which to explore the effects of maternal obesity and diet on offspring body weight. Avy/a mice are spontaneously hyperphagic and develop adult-onset obesity. Severity of obesity, however, is highly variable among isogenic Avy/a mice. The overall hypothesis of the proposed research is that maternal obesity during pregnancy and/or lactation affects the establishment of gene-specific DNA methylation patterns in the developing hypothalamus, causing permanent changes in hypothalamic gene expression, food intake regulation, and body weight.
The specific aims of this project are to: 1) characterize the developmental establishment and tissue-specificity of DNA methylation at hypothalamic genes that affect food intake regulation, 2) in the Avy mouse model, determine if the effects of maternal obesity on offspring body weight occur during prenatal or early postnatal development, and 3) determine if methylation and expression of specific genes in the hypothalamus of adult Avy/a mice are correlated with obesity. This research in animal models is necessary to elucidate the mechanisms by which maternal obesity affects offspring body weight;this information will enable us to accurately gauge the impact of such phenomena on the etiology of human obesity and potentially design effective interventions.
The overall hypothesis of the proposed research is that maternal obesity during pregnancy and/or lactation affects the establishment of gene-specific DNA methylation patterns in the developing hypothalamus, causing permanent changes in hypothalamic gene expression, food intake regulation, and body weight. We will investigate this hypothesis in mice with and without a genetic predisposition to obesity. Our results will elucidate the mechanisms by which maternal obesity affects offspring body weight, enabling us to accurately gauge the impact of such phenomena on the etiology of human obesity and, eventually, design effective interventions.
|Silver, Matt J; Kessler, Noah J; Hennig, Branwen J et al. (2015) Independent genomewide screens identify the tumor suppressor VTRNA2-1 as a human epiallele responsive to periconceptional environment. Genome Biol 16:118|
|Yu, Da-Hai; Gadkari, Manasi; Zhou, Quan et al. (2015) Postnatal epigenetic regulation of intestinal stem cells requires DNA methylation and is guided by the microbiome. Genome Biol 16:211|
|Baker, M S; Li, G; Kohorst, J J et al. (2015) Fetal growth restriction promotes physical inactivity and obesity in female mice. Int J Obes (Lond) 39:98-104|
|Kunde-Ramamoorthy, Govindarajan; Coarfa, Cristian; Laritsky, Eleonora et al. (2014) Comparison and quantitative verification of mapping algorithms for whole-genome bisulfite sequencing. Nucleic Acids Res 42:e43|
|Li, Ge; Zhang, Wenjuan; Baker, Maria S et al. (2014) Major epigenetic development distinguishing neuronal and non-neuronal cells occurs postnatally in the murine hypothalamus. Hum Mol Genet 23:1579-90|
|Waterland, Robert A (2014) Epigenetic mechanisms affecting regulation of energy balance: many questions, few answers. Annu Rev Nutr 34:337-55|
|Yu, Da-Hai; Waterland, Robert A; Zhang, Pumin et al. (2014) Targeted p16(Ink4a) epimutation causes tumorigenesis and reduces survival in mice. J Clin Invest 124:3708-12|
|Dominguez-Salas, Paula; Moore, Sophie E; Baker, Maria S et al. (2014) Maternal nutrition at conception modulates DNA methylation of human metastable epialleles. Nat Commun 5:3746|
|Li, Ge; Kohorst, John J; Zhang, Wenjuan et al. (2013) Early postnatal nutrition determines adult physical activity and energy expenditure in female mice. Diabetes 62:2773-83|
|Zeisel, Steven H; Waterland, Robert A; Ordovas, Jose M et al. (2013) Highlights of the 2012 Research Workshop: Using nutrigenomics and metabolomics in clinical nutrition research. JPEN J Parenter Enteral Nutr 37:190-200|
Showing the most recent 10 out of 17 publications