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Prevention and Therapy of Type 2 Diabetes by Selective Modulation of the Human Peroxisome Proliferator-Activated Receptor Gamma (Pparγ)

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Prevention and Therapy of Type 2 Diabetes by Selective Modulation of the Human Peroxisome Proliferator-Activated Receptor Gamma (Pparγ) Prevention and therapy of type 2 diabetes by selective modulation of the human peroxisome proliferator-activated receptor gamma (PPARγ) Dissertation zur Erlangung des akademischen Grades des Doktors der Naturwissenschaften (Dr. rer. nat.) eingereicht im Fachbereich Biologie, Chemie, Pharmazie der Freien Universität Berlin vorgelegt von Dipl.- Biochem. Christopher Weidner aus Berlin Juni 2011 Die Dissertation wurde in der Zeit von Januar 2008 bis Juni 2011 im Max-Planck- Institut für molekulare Genetik in Berlin in der Arbeitsgruppe Nutrigenomics and Gene Regulation unter der Leitung von Dr. Sascha Sauer angefertigt. 1. Gutachter: Dr. Sascha Sauer Max-Planck-Institut für molekulare Genetik 2. Gutachter: Prof. Dr. Markus Wahl Freie Universität Berlin Disputation am: Acknowledgements I am deeply grateful to my advisor Dr. Sascha Sauer for giving me the opportunity to freely develop my research study on PPARγ, for supporting me with inspiring discussions, encouragement and guidance, and for reviewing this thesis. I also thank Prof. Dr. Markus Wahl for reviewing this work. I like to express my gratitude to my colleagues for their technical support, scientific discussions and daily encouragements. My special thanks are to Anja Freiwald and Radmila Feldmann. For their commendable technical assistance during the animal studies I am very grateful to Katharina Hansen, Ulf Schröder and Dr. Ludger Hartmann. I am thankful to Prof. Dr. Frank C. Schroeder for essential chemical synthesis of the amorfrutins, to Jens C. de Groot and Dr. Konrad Büssow for excellent crystallography of the PPARy-amorfrutin complex, and to Dr. Matthias Baumann for pharmacological experiments. I am further grateful to Prof. Dr. Annette Schürmann and Prof. Dr. Andreas F. Pfeiffer for fruitful discussions. My special thanks are to my dear wife Nicole and to my cute sons Jonathan and Theodor for their encouragement, sympathy, and love. This work was supported by the German Federal Ministry of Education and Research (BMBF) and the Max Planck Society. Contents 1 Introduction ......................................................................................... 7 1.1 The diabetic epidemic – a challenge for the 21st century....................... 7 1.2 Going hand in hand: Insulin resistance, obesity and inflammation........ 8 1.2.1 Evolutionary considerations.......................................................... 8 1.2.2 Insulin resistance........................................................................... 9 1.2.3 Obesity........................................................................................... 10 1.2.4 The connection between diabetes, obesity & inflammation.......... 11 1.2.5 The role of pathogens.................................................................... 15 1.3 Nuclear receptors.................................................................................... 16 1.3.1 The peroxisome proliferator-activated receptor (PPAR) .............. 19 1.3.1.1 PPARα............................................................................... 20 1.3.1.2 PPARβ/δ............................................................................ 21 1.3.1.3 PPARγ ............................................................................... 22 1.4 Pharmacological treatment of type 2 diabetes........................................ 27 1.5 Prevention of type 2 diabetes ................................................................. 29 1.6 Mother Nature’s medicine chest- Natural products in drug discovery... 30 1.7 Aims of this thesis.................................................................................. 33 2 Materials and Methods ....................................................................... 35 2.1 Compounds and natural products........................................................... 35 2.2 Chemical synthesis of amorfrutins......................................................... 35 2.3 Time-resolved FRET assays................................................................... 36 2.4 Reporter-gene assay................................................................................ 37 2.5 Crystallization and structure determination............................................ 38 2.6 Cell culture ............................................................................................. 39 2.7 PPARγ knockdown ................................................................................ 39 2.8 RNA purification, cDNA synthesis and qPCR....................................... 40 2.9 Viability assays....................................................................................... 42 2.10 Genome-wide gene expression analyses ................................................ 42 2.11 Animal studies........................................................................................ 44 2.12 Metabolic parameters measurements ..................................................... 46 2.13 Immunoblotting...................................................................................... 47 2.14 Statistical analyses.................................................................................. 48 2.15 Equipment and reagents ......................................................................... 48 2.15.1 Reagents ...................................................................................... 48 2.15.2 Cells and animals ........................................................................ 51 2.15.3 Equipments and consumables ..................................................... 52 2.15.4 Software....................................................................................... 53 3 Results................................................................................................... 54 3.1 From plant to tube: In vitro characterization of novel PPAR ligands.... 54 3.1.1 Amorfrutins are a novel class of PPAR-binding natural products 54 3.1.2 Amorfrutins partially recruit transcriptional cofactors to PPARγ. 57 3.1.3 Amorfrutins partially activate PPARγ in cell culture.................... 59 3.2 From tube to bench: Effects of amorfrutins in target cells .................... 59 3.2.1 Amorfrutins induce expression of PPARγ targets in adipocytes... 59 3.2.2 PPARγ knockdown confirms selectivity of amorfrutins............... 60 3.2.3 Amorfrutins regulate metabolism and immunity in adipocytes .... 61 3.2.4 Amorfrutins are selective PPARγ modulators (SPPARγMs)........ 70 3.2.5 Amorfrutins show promising ADMET properties ........................ 72 3.3 From bench to mouse: Animal studies .................................................. 72 3.3.1 Amorfrutin 1 has a safe profile on liver toxicity in mice .............. 73 3.3.2 Amorfrutin 1 reduces insulin resistance, dyslipidemia and obesity in DIO mice................................................................ 73 3.3.3 Amorfrutin 1 prevents development of insulin resistance and dyslipidemia in HFD-fed mice............................................... 77 3.3.4 Amorfrutin 1 ameliorates insulin sensitivity and dyslipidemia in db/db mice..................................................... 78 3.3.5 Amorfrutin 1 inhibits HFD-induced PPARγ phosphorylation...... 79 3.3.6 Amorfrutin 1 reduces detrimental deposit of lipids in various tissues........................................................................... 81 3.3.7 Amorfrutin 1 has protective effects on pancreas........................... 83 3.3.8 Amorfrutin 1 promotes expression of genes of lipid breakdown.. 84 3.3.9 Amorfrutin 1 reduces HFD-induced inflammation and macrophage invasion.............................................................. 85 4 Discussion............................................................................................. 87 4.1 The amorfrutin structure......................................................................... 87 4.2 The in vitro properties of amorfrutins .................................................... 91 4.3 Cell culture studies with amorfrutins ..................................................... 94 4.4 The effects of amorfrutins in mice ......................................................... 95 4.5 Future perspectives................................................................................. 99 4.5.1 Further studies............................................................................... 99 4.5.2 Pharmaceutical applications of amorfrutins .................................. 101 4.5.3 Nutraceutical applications of amorfrutins..................................... 103 5 Summary .............................................................................................. 105 6 Zusammenfassung ............................................................................... 106 7 References ............................................................................................ 107 8 Abbreviations....................................................................................... 125 9 Supplementary Data............................................................................ 129 9.1 Supplementary Figures........................................................................... 129 9.2 Supplementary tables.............................................................................. 135 Introduction - 7 1 Introduction 1.1 The diabetic epidemic – a challenge for the 21st century 30 million, 135 million, 217 million - the worldwide prevalence of diabetes in 1985, 1995 and 2005 reached an alarming epidemic state and is estimated to
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