Obesity and Intraepithelial Lymphocyte Dysfunction

Abstract

Abstract Obesity has become prevalent in the United States with over 30% of adults and 17% of children having a BMI over 30. Complications associated with obesity include chronic nonhealing wounds in the skin and increased susceptibility to more severe colitis in the intestine suggesting that obesity leads to barrier dysfunction. Intraepithelial lymphocytes regulate epithelial homeostasis through the production of growth factors and cytokines. Our laboratory has shown that obese mice exhibit reduced numbers of intraepithelial lymphocytes in both the skin and the intestine. The remaining intraepithelial lymphocytes have reduced growth factor and cytokine production resulting in dysregulation of the barrier. To better understand the mechanism of T cell dysfunction, we placed mice on high-fat diet immediately post-weaning when intraepithelial lymphocytes are seeding the intestine. After 7 weeks, mice fed normal chow had normal numbers of intraepithelial lymphocytes seeding the intestine, however mice fed a high-fat diet had almost 50% fewer cells. CCR9 and CD103 were both reduced on the lymphocytes suggesting problems with homing and retention. In addition, mice administered a high-fat diet were more susceptible to DSS-induced colitis. To determine whether intestinal epithelial cells could be restored to normal numbers in obese mice, obese mice were administered normal chow for 7 weeks. Indeed, reducing fat intake was sufficient to restore intraepithelial lymphocytes to normal levels and rescue mice from more severe colitis suggesting that dieting is effective in improving intestinal barrier function in obesity.