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3 Chapter One. Introduction  7 1.1. Molecular Mechanisms of Insulin and Glucagon Action  7 1.2. Metabolic Syndrome and Insulin Resistance  10 1.3.1. Liver in the insulin resistant state  16 1.3.2. Pancreas in the insulin resistant state  17 1.4. Role of HATs, HDACs in metabolism  20 1.5. Foxa2 in Development and Metabolism  23 1.5.1. Foxa2 in Liver  24 1.5.2. Foxa2 in Pancreas  27 Chapter Two. Liver overexpression of Foxa2 acetylation mutants improves glucose homeostasis in diabetic animal models  29 Background  29 Aims of the study  30 2.1. Foxa2 acetylation-mimicking but not Foxa2-acetylation deficient mutant improve glucose homeostasis in genetically obese db/db males upon virus-mediated liver overexpression of the mutant protein.  31 Discussion  36 Chapter Three. Analysis of Foxa2QQ Liver Knockin  38 Background  38 Aims of the study  38 3.1. Cloning of Foxa2QQ mutant  39 3.2. ES cell targeting of Foxa2 acetylation mutants  42 3.3. Biochemical analysis of Foxa2-acetylation-mimicking knockin mice.  44 3.3.1. Foxa2QQ liver-specific knockin exhibit lower gluconeogenesis program after re-feeding with unchanged glucose output.  44 3.3.2. Liver insulin sensitivity markers and Foxa2 protein stability are unaffected in Foxa2QQ knockin livers and hepatocytes.  49 3.4. Cohort analysis of Foxa2QQ liver-specific knockin  54 3.4.1. Foxa2QQ liver-specific knockin mice display weight and blood glucose levels similar to those of controls on chow and high fat diet  54 3.4.2. Foxa2QQ mice and controls display similar glucose metabolism parameters on chow and high fat diet  56 3.4.3. Lipid metabolism is unchanged in Foxa2QQ liver-specific knockin  63 Discussion  67 Chapter Four. Analysis of Foxa2QQ Pancreas Knockin Mutant  73 Background  73 Aim of the study  73 4.1. Foxa2QQ islet-specific knockin grants no protection against HFD-induced glucose impairments  73 Discussion  80 Chapter Five. Impact of Acetylation on Protein Functionality  82 Chapter Six. Materials and Methods  88 6.1. Mouse work  88 6.2. Plasma Analysis  89 6.3. Tissue and cell analysis  91 List of Abbreviations  96 Bibliography  99

Role of Foxa2 Acetylation in Diabetes and Obesity in Vivo