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GRK 1482 Jahrbuch 2011-2014

Abstract It has been published that diet induced obesity is associated with low-grade inflammation and leads to changes of the gut barrier in- tegrity and to an induction of the unfolded protein response due to a disrupted protein homeostasis. The aim of the PhD thesis is to elucidate the connection between diet-induced obesity, gut barrier and adipose tissue function as well as intestinal inflammatory processes on the genetic background of three inbred mouse strains which were differently sensitive to high-fat diets and additionally gut/adipose- specific knockout/transgenic mouse models. Introduction The incidence of overweight and obese people has dramatically increased during recent decades. A high caloric intake in humans is associated with an increased incidence of degenerative processes such as chronic inflammatory disorders of the gas- trointestinal tract as well as metabolic diseases like insulin resistance or type 2 diabetes [1]. It has been reported that a high-fat diet (HFD) leads to an impaired gut barrier function [2]. We could also observe that HFD accelerates the on- set of Crohn’s disease, a type of inflammatory bowel disease, in an ileitis mouse model [3]. However it is still not clarified if the changed intestinal perme- ability is the cause or the consequence of inflam- matory processes in the gut. Therefore three dif- ferent inbred mouse models were used which respond differently to fat-enriched diet. The first mouse model is SWR/J which is resistant to diet- induced obesity. C57Bl/6J mice are susceptible and AKR/J mice are even more sensitive to high-fat feeding. Inflammatory processes or high-fat diets can also trigger unfolded protein response (UPR). UPR con- tributes to the protein folding capacity of cellular organelles such as mitochondria and adaptation of organ functions in response to diet- and dis- ease-related challenges including metabolically- associated disorders. Disruption of mitochondrial homeostasis due to the loss of adequate UPR mechanisms may contribute to the development of obesity-related co-morbidities such as insulin resistance and failure of glucose and fat metabo- lism [4]. The accumulation of unfolded protein within the mitochondrial matrix results in the upregulation of nuclear genes encoding mitochondrial UPR-related proteins such as chaperonin 60 (HSP60) and its transcriptional regulator C/EBP homologous pro- tein (CHOP) [5]. It should be examined the role of the chaperone HSP60 and CHOP in gut and peri- pheral adipose tissue depots under normal and fat- enriched conditions using constitutive and induc- ible expression of Cre recombinase (Villin-Cre and Adiponectin-Cre mice). ASSOCIATED FELLOWS Page 72 | GRK Progress Report 2011-2014 Valentina Schüppel (Dipl. Biol.) Nutrition and Immunology PhD The impact of high-fat feeding on gut barrier and metabolic function