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GRK 1482 Jahrbuch 2011-2014

Publications [1] Cani et al. Metabolic Endotoxemia Initiates Obesity and Insulin Resistance. Diabetes. 2007, 56: 1761-1772. [2] Cani et al. Changes in Gut Microbiota Control Metabo- lic Endotoxemia-Induced Inflammation in High-Fat Diet- Induced Obesity and Diabetes in Mice. Diabetes. 2008, 57: 1470-1481. [3] West et al. Dietary obesity in nine inbred mouse strains. Am J Physiol. 1992, 262: R1025-32. Outlook To test the impact of HFD on the intestinal barrier, it is planned to repeat experiments after a longer and shorter feeding period (1 and 12 weeks HFD) and with two different diets: The quantity of fat in the diet should be increased: 48 kJ% 60 kJ% fat and also the quality, meaning the fat source will be changed: plant (palm oil) animal (lard). Additionally, insulin tolerance tests, histological and gene expression analysis of the adipose tissue will be performed in AKR/J and SWR/J mice at time points of different adipose tis- sue status (anabolic, catabolic). ASSOCIATED FELLOWS GRK Progress Report 2011-2014 | Page 69 Aim By measuring the intestinal barrier and glucose tolerance in mouse strains with different susceptibility to DIO I elucidate the relative contribution of the factors diet and obesity. These read- outs will be studied at different time points of HFD feeding and during caloric restriction to analyze cause and consequence as well as the reversibility of HFD and/or DIO effects. Methods and Results In the pioneer experiment, male AKR/J, SWR/J and C57BL/6J mice were fed HFD (48 kJ% fat) or control diet (CD, 12 kJ% fat) for 4 weeks. The mice increased their body mass, especially fat mass, as expected: AKR/J > B/6J > SWR/J. DIO prone mice showed impaired oral glucose tolerance (GT) although there was no evidence for an altered intestinal barrier, neither ex vivo (compare V. Schüppel) nor in vivo (recovery of orally adminis- tered Polyethylene Glycol in 16 h urine measured by HPLC by M. Lichtenegger). Glucose (2.8 g glucose/kg lean mass) was administered orally after 6 h fasting and blood glucose levels were measured 0, 15, 30, 60, 120 min after gavage. In the second setup the mice received HFD or CD for 12 weeks, followed by either refeeding of CD or restricted pair-feeding with HFD. Body mass, body composition by nuclear magnetic reso- nance, energy intake, energy expenditure by indirect calorimetry and oral GT were measured regularly. Energy expenditure was increased in HFD fed animals of all strains, but in AKR/J and B/6J not sufficiently to defend their body mass. Acutely, HFD feeding for 1.5 days increased ener- gy intake and reduced GT in all three strains. During prolonged HFD feeding, DIO prone AKR/J and B/6J mice, but not DIO re- sistant SWR/J mice, maintained impaired GT. Refeeding CD or pair-feeding HFD of obese AKR/J mice normalized GT rapidly after one week. So far, these results demonstrate that HFD does not alter the in- testinal barrier but HFD triggers a fast reduction of GT, indepen- dent of DIO susceptibility. This is an acute metabolic response to the increased utilization of fatty acids as energy substrates. Impaired GT is only maintained in mouse strains prone to DIO suggesting an important contribution of anabolic metabolism of adipocytes whereas shifting towards a catabolic state of adi- pocytes rapidly normalizes GT. All DIO effects seem not to be pathological due to the reversibility. Figure: Body mass of AKR/J and SWR/J mice during the feeding trial (A). At the age of 12 weeks the animals received HFD or CD. After 12 weeks feeding, the HFD mice are refed CD or pair-fed (pf) the same amount of energy as the refed group in forms of HFD. Oral glucose tolerance was measured after 1.5 days (age 12,2 weeks), 12 weeks (age 24 weeks) HFD and one weeks after refeeding or pair-feeding (age 25 weeks). The tolerance is indicated as the area under the curve (AUC)(B). Error bars represent the standard deviation of the mean, asterisks indicate signifi- cant difference (two�tailed student’s t�test *p < 0.05), n=8-10. Supervisors Prof. Dr. Martin Klingenspor I TUM I Molecular Nutritional Medicine Start of project: February 2011 Academic background: Studies of Nutritional Science at Technische Universität München