Masters Thesis

The Impact of Obesity on Intestinal Epithelial T Cell Number and Function in Mice in Different Stages of Maturity

According to the Journal of the American Medical Association and the Centers for Disease Control and Prevention, one in six children and adolescents in the United States are obese. Obesity is a metabolic disease caused by a caloric imbalance, which leads to an accumulation of excess fat in the body. Adipose tissue constitutes an endocrine organ that can become unregulated as it expands and cause chronic systemic inflammation. There is a strong correlation between obesity and inflammatory conditions such as inflammatory bowel disease. In addition, the gastrointestinal problems encountered in obese youth are more severe than in patients whose obesity manifests in adulthood. Although intraepithelial lymphocytes are known to improve intestinal barrier function and decrease the severity of inflammatory bowel disease, it is unknown whether intraepithelial lymphocytes are impacted by obesity. An established murine model of obesity was used to examine the relationship between the developmental stage of obesity onset and the ability of intraepithelial lymphocytes to seed in the intestine, maintain normal numbers and function in barrier protection. Since intraepithelial lymphocytes seed in the intestine early in childhood and proliferate locally to produce numbers that are maintained throughout adulthood, we hypothesized that these immune cells may be especially sensitive to obesity at an early age. Immunohistochemistry and flow cytometry were used to examine intraepithelial T cell number and function in the intestine of mice that experienced controlled onsets of obesity at stages similar to child, adolescence, and adulthood of humans. Intraepithelial lymphocytes were significantly reduced in all three stages of maturation after consuming a high fat diet. Obese weanling mice exhibited the fewest intraepithelial lymphocytes as compared to the obese adolescent and obese adult mice. However, T cell subsets in adolescent and adult mice were more severely skewed toward inflammatory populations with elevated TNF-a production than T cell subsets in weanling mice. Both factors may result in problems with barrier function and contribute to the increased severity of inflammatory bowel disease. Together these results demonstrate that the age at which weight gain is initiated is important in the pathogenesis of intestinal disease in obesity.

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