A systems biology analysis of adrenergically stimulated adiponectin exocytosis in white adipocytes

ABSTRACT Circulating levels of the adipocyte hormone adiponectin are typically reduced in obesity and this deficiency has been linked to metabolic diseases. It is thus important to understand the mechanisms controlling adiponectin exocytosis. This understanding is hindered by the high complexity of the data and the underlying signalling network. To handle this complexity, we here analyse the data using systems biology mathematical modelling. Previously, we have developed a mathematical model for how different intracellular concentrations of Ca2+, cAMP and ATP affect adiponectin exocytosis (measured as increase in membrane capacitance). However, recent work has shown that adiponectin exocytosis is physiologically triggered via signalling pathways involving adrenergic β3 receptors (β3ARs). Therefore, we have herein developed a more comprehensive model that also includes adiponectin exocytosis stimulated by extracellularly applied adrenaline or the β3AR agonist CL 316,243. Our model can explain all previous patch-clamp data, as well as new data consisting of a combination of the intracellular mediators and extracellular adrenergic stimuli. Without changing the parameters, the model can accurately predict independent validation data with other combinations of patch-clamp pipette solutions and external stimuli. Finally, we use the model to perform new in silico experiments examining situations where corresponding wet lab experiments are difficult to perform. By this approach, we simulated adiponectin exocytosis in single cells, in response to the reduction of β3ARs that is observed in adipocytes from animals with obesity-induced diabetes. Our work brings us one step closer to understanding the intricate regulation of adiponectin exocytosis.