A comprehensive dynamic model of the adipocyte

The adipose tissue contributes to energy homeostasis by storing excess energy as triglycerides when the energy status is high, and by releasing fatty acids when the energy status is low. In addition to the involvement in energy homeostasis, the adipose tissue also has a function of hormonal control exerted by the release of adipokines such as adiponectin. Dysregulations in the signaling pathways of these two functions are involved in the development of type 2 diabetes and related complications such as cardiovascular disease. These signaling pathways are too complex to be fully unraveled without a systematic framework, such as mathematical modeling. Previous modeling works have investigated the insulin signaling pathways leading to glucose uptake in primary human adipocytes in response to insulin stimulation. Furthermore, experimental works have investigated how adrenergic stimuli and varying concentrations of intracellular mediators triggers the release of adiponectin from 3T3‐L1 adipocytes, and how insulin and adrenergic stimuli influence lipolysis in primary human adipocytes. Additionally, large‐scale phosphoproteomic data for insulin signaling in 3T3‐L1 adipocytes have become available. However, these experimental data had not been systematically investigated using mathematical modeling. In this thesis, I have used mathematical modeling to study three aspects of the adipocyte: 1) adiponectin release, 2) lipolysis, and 3) intracellular crosstalk between the pathways of glucose uptake, lipolysis, and adiponectin release. Finally, I have developed a new method for automatic model expansion. In Paper I, we used mathematical modeling to test a hypothesis of the mechanisms controlling adiponectin exocytosis in 3T3‐L1 cells. We found that the hypothesis had to be revised in order to be in agreement with the available experimental data. We used the revised model to quantify the balance between the exocytosis and the endocytosis, and to predict the amount of released adiponectin in response to additional experiments. In Paper II, we extended the adiponectin exocytosis model from Paper I with mechanisms for how extracellular adrenergic stimulation trigger adiponectin exocytosis. We also used the model to quantify the effect of a decreased amount of β3‐adrenergic receptors on the adrenergically stimulated adiponectin exocytosis. In Paper III, we tested a hypothesis of the impact of, and crosstalk between, insulin and adrenergic stimulation on the lipolysis. We used the model to test three different actions by insulin on the lipolysis, and to predict fatty acid release in vivo in response to stimulations with epinephrine and insulin. In Paper IV, we combined the models from Paper I‐III with a previously published model for glucose uptake. We then used the connected model as a core model to which additional signaling data could be added using a new method for automatic model expansion. This new method incorporates prior‐knowledge and large‐scale data to expand a core model with thousands of additional phosphosites into a comprehensive model of the adipocyte. The comprehensive expanded model can propagate the effect of type 2 diabetes from the core model to a substantial part of the phosphoproteome, and could thus facilitate the finding of new drug targets or treatment regimens for type 2 diabetic patients