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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK081557-05
Application #
8308661
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Hyde, James F
Project Start
2008-08-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$275,798
Indirect Cost
$58,608
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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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; 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
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Yu, Da-Hai; Ware, Carol; Waterland, Robert A et al. (2013) Developmentally programmed 3' CpG island methylation confers tissue- and cell-type-specific transcriptional activation. Mol Cell Biol 33:1845-58
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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

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