1. Centre for Medical Systems Biology Jan Bert van Klinken, LUMC

2. 26-02-2010Modelling Whole Body Metabolism2 Introduction Aim Development of a mathematical model of whole-body metabolism, in relation to metabolic syndrome (obesity, dyslipidemia, high blood pressure, insulin resistance,...) At LUMC focus on whole-body level. At TU/e focus on cellular level. ?

3. 26-02-2010Modelling Whole Body Metabolism3 The hyperinsulinemic-euglycemic clamp Insulin resistance: a condition in which normal amounts of insulin are inadequate to produce a normal insulin response in muscle, liver and fat cells Plasma glucose INSULIN INFUSION GLUCOSE INFUSION + - LIVER PERIPHERAL TISSUES

4. 26-02-2010Modelling Whole Body Metabolism4 Indirect Calorimetry Metabolic flexibility: the ability to adapt fuel selection to fuel availability glucose C 6 H 12 O 6 + 6O 2  6CO 2 + 6H 2 O RER = 1.0 tripalmitin 2 C 51 H 98 O 6 + 145O 2  102CO 2 + 98H 2 O RER = 0.7 1 0.7 Carb Fat

5. 26-02-2010Modelling Whole Body Metabolism5 Modelling Approach Mathematical model will be based on that of Hall, which explains at a macrolevel how changes in body weight and composition result from changes in food intake. Existing model will be extended with more detailed regulation mechanisms for glucose and fat homeostasis and organ specificity. Hall (2006) Am J Physiol Endocrinol Metab

6. 26-02-2010Modelling Whole Body Metabolism6 Modelling Approach In order to be better able to validate the mathematical model, existing experimental techniques and methods for data analysis are being optimised. - relate time patterns in variables measured by metabolic cage (food intake, physical activity, O 2 and CO 2 exchange) by means of digital signal processing techniques. - refine calculations of macronutrient oxidation rates (from O 2 and CO 2 exchange) for specific diet compositions, such that whole-body energy balance can be deduced. - perform clamp and other tracer experiments with stable isotopes in order to get a more comprehensive picture of macronutrient flows and their regulation.

7. 26-02-2010Modelling Whole Body Metabolism7 Summary * Main focus in our Systems Biology approach lies on quantitative understanding * Dynamic mathematical models simple (typically few dynamic variables) * Heterogeneous experimental data: metabolic cage, dexa scan, clamp, tracer experiments, Western blot * Broad range of analysis techniques: digital signal processing, statistics, stoichiometric analysis (simulation, control analysis)