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GRK 1482 Jahrbuch 2011-2014

Abstract Integrity of the endothelial and epithelial barrier is a requirement for maintaining gut homeostasis and digestive health. Dysregulation of endothelial and epithelial barrier occurs in a variety of disease states including inflammation, obesity, and diabetes. The molecular and phy- siological impact of different high-fat diets and fatty acids, such as n-3 long-chain polyunsaturated fatty acids, on epithelial and vascular gene expression and functions in the small intestine and adjacent me- senteric fat will be determined in DIO mice. Introduction In obesity, mesenteric adipose tissue has been im- plicated in the pathophysiology of intestinal and mesenteric diseases, e.g. creeping fat in Crohn’s disease, indicating a crosstalk between the intes- tine and the adipose tissue [1]. In inflammatory bowel disease, cytokine-mediated inflammation and epithelial apoptosis are involved in disturbing the intestinal barrier causing inflammation and pro- voking endothelial microvascular permeability [1,2]. Predominantly in vitro studies have reported that saturated fatty acids can corrupt barrier function by increasing the intestinal epithelial and endothe- lial activation and permeability, whereas n-3 long- chain polyunsaturated fatty acids (n-3 LC-PUFA) can improve barrier function. However, the impact of fatty acids on barrier functions in vivo and the functional link between impaired intestinal barriers and obesity and diabetes are less clear [3,4]. In the previous GRK-PhD15/1 project, using our diet-induced obesity (DIO) mouse model, we have shown that, compared to high-fat diet (HF), high- fat diet enriched with n-3 LC-PUFA (HF/n-3) causes significant anti-adipogenic effects [5]. Additionally, gene and protein expression analyses demonstra- ted differential pro- and anti-inflammatory gene expression in mesenteric and epididymal adipose tissues and diet-dependent changes in endothelial cell activation in the small intestine [5]. Moreover, subsequent gene expression array analyses indica- ted expression changes of genes involved in nitric oxide (NO) production and oxidative stress in the small intestine. Abnormalities in vascular NO pro- duction due to obesity and oxidative stress can result in vascular dysfunction. It has been shown that saturated fatty acids impair endothelial NO pro- duction whereas n-3 PUFAs increase NO produc- tion. In our project, we will assess whether feeding mice different high-fat and control diets changes thepermeabilityofepithelialandendothelialbarriers in the small intestine and impacts the mesenteric vasculature, which is functionally connected with the intestinal vasculature. For our analysis, molecu- lar and physiological approaches will be performed. ASSOCIATED FELLOWS Page 78 | GRK Progress Report 2011-2014 Stefanie Worsch (M.Sc.) Nutritional Medicine PhD 15/2 Effects of diet-induced obesity (DIO) and n-3 LC-PUFA on epithelial and endothelial barriers in the small intestine and mesenteric adipose tissue of mice