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Abstract
Obesity is a complex disease involving interactions between genetics and the environment. Epigenetic modifications are able to integrate changes in the environment (i.e. diet) into the genomes of cells. This dissertation identifies distinct leukocyte type specific changes in DNA methylation that are associated with obesity. Three studies were performed to (1) identify which peripheral leukocyte types may be the best to assess DNA methylation in response to a phenotype, (2) examine the DNA methylation profile of CD4+ T cells, CD8+ T cells, and CD16+ neutrophils in obese and normal weight women, and (3) examine the DNA methylation profile in CD4+ T cells in overweight and obese women before and after a weight loss intervention. In all studies of this dissertation, cell type specific differences in regards to their DNA methylome were observed. The first study (Chapter 2) identified that CD4+ T cells, CD8+ T cells, and CD14+ monocytes are the most potentiated to respond to physiological cues via their methylomes. Thus, CD4+ T cells and CD8+ T cells were selected for analysis in obese women, as well as a third leukocyte type, CD16+ neutrophils, which were found to be less potentiated to respond, but are the majority leukocyte type. In the obese women DNA methylation was found to be altered in 19 sites in CD4+ T cells and 16 sites in CD8+ T cells, while no alterations were identified in neutrophils (q<0.05) (Chapter 3). Additionally, in the CD4+ T cells, 79 sites were identified to have methylation levels correlated with the amount of visceral adipose tissue (q<0.05). When DNA methylation was examined in relation to weight loss in CD4+ T cells (Chapter 4), 448 sites were identified to have methylation levels post-intervention that were associated with the amount of android fat lost over the intervention (q<0.05). Changes in DNA methylation associated with weight loss were only observed in the women who began the intervention with the lowest amount of android fat. Collectively the studies of this dissertation provide evidence that there are leukocyte type specific alterations in DNA methylation that are associated with obesity.