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GRK 1482 Jahrbuch 2011-2014

Publications [1] Cone RD. Anatomy and regulation of the central mela- nocortin system. Nat Neurosci. 2005, 8(5):571-8. [2] Cheng CY, Chu JY, Chow BK. Central and peripheral administration of secretin inhibits food intake in mice through the activation of the melanocortin system. Neuropsychopharmacology. 2011, 36(2):459-71. doi: 10.1038/npp.2010.178. Epub 2010 Oct 6. [3] Bolze F, Rink N, Brumm H, Kühn R, Mocek S, Schwarz AE, Kless C, Biebermann H, Wurst W, Rozman J, Klingenspor M. Characterization of the melanocortin- 4-receptor nonsense mutation W16X in vitro and in vivo. Pharmacogenomics J. 2013, 13(1):80-93. doi: 10.1038/ tpj.2011.43. Epub 2011 Oct 4. [4] Pimentel GD, Micheletti TO, Pace F, Rosa JC, Santos RV, Lira FS. Gut-central nervous system axis is a target for nutritional therapies. Nutr J. 2012, 11:22. doi: 10.1186/1475-2891-11-22. PhD FELLOWS GRK Progress Report 2011-2014 | Page 55 Aim The aim of the study is to characterize and examine the effects of secretin administrations on energy balance to find out about involved components and influencing mechanisms. Further- more the effects of energy metabolism influencing hormones (secretin, leptin, ghrelin and melanocortin agonists) will be compared in different mouse strains with variable susceptibility for diet-induced obesity. Methods and Results The influence of secretin on food intake will be determined by using different mouse models and experimental settings. The characteristics of the mechanism will be analyzed in: • mice showing disrupted melanocortin-4-receptor expression (Mc4rw16x-mice, Bolze et al., 2013) • feeding models (HFD vs. CD) • interperitoneal (i.p.) vs. intra cerebroventricular (i.c.v.) injec- tions • Three different inbred mouse lines (AKR/J, SWR/J and C57BL6/J strain) In our experiments we want to show, that the effect of secre- tin on food intake is mediated by the Mc4r and not by another receptor of the MC-system. Furthermore we want to de-termine the sensibility of the anorectic effect by using different admi- nistration techniques and feeding models. The different mouse lines are used as a polygenic model to test whether secretin- signaling could play a role in susceptibility to diet-induced ob- esity. For AKR/J, SWR/J and C57BL6/J some coding polymorphisms between the strains are known for the secretin-receptor. There- fore the receptors of the three mouse strains will be cloned and overexpressed in HEK-cells to examine the activation of the cells by secretin. Additionally the influence of further energy-homeostasis rela- ted hormones will be analyzed in mice of the AKR/J, SWR/J and of the C57BL6/J strains. The mice will be treated with either: • Leptin • Melanocortin agonists • Ghrelin After injection the mice will be examined for food intake, body weight, oxygen consumption and respiratory ratio in order to find mouse strain specific differences. Outlook Initially secretin-injections with the Mc4rw16x-mice will com- pared to wildtype mice to test the possible Mc4r-dependence. Additionally cell culture experiments will be carried out to com- pare the sensitivity of the secretin-receptors of the three diffe- rent mouse strains. Furthermore the three mouse strains will be tested as polygenic model for their sensitivity for leptin, me- lanocortin agonists and ghrelin injections by measuring food intake and oxygen consumption. Figure: Role of gut-hormones on regulation of energy intake in fasted and fed state. Fasting and feeding hormones reach the arcuate nucleus (ARC) in the hypothalamus and modulate the acticity of orexigenic Agrp- neurons or anorexigenic POMC-neurons. Both neuron-types project to second-order neurons (modified from Pimentel et al. 2012). Supervisors Prof. Dr. Martin Klingenspor I TUM I Molecular Nutritional Medicine Prof. Dr. Michael Schemann I TUM I Human Biology Start of project: August 2011 Academic background: Studies of Nutritional Science at Technische Universität München