Mathematical modeling of white adipocyte exocytosis predicts adiponectin secretion and quantifies the rates of vesicle exo- and endocytosis

Abstract

Adiponectin is a hormone secreted from white adipocytes and takes part in the regulation of several metabolic processes. Although the pathophysiological importance of adiponectin has been thoroughly investigated, the mechanisms controlling its release are only partly understood. We have recently shown that adiponectin is secreted via regulated exocytosis of adiponectin-containing vesicles, that adiponectin exocytosis is stimulated by cAMP-dependent mechanisms, and that Ca and ATP augment the cAMP-triggered secretion. However, much remains to be discovered regarding the molecular and cellular regulation of adiponectin release. Here, we have used mathematical modeling to extract detailed information contained within our previously obtained high-resolution patch-clamp time-resolved capacitance recordings to produce the first model of adiponectin exocytosis/secretion that combines all mechanistic knowledge deduced from electrophysiological experimental series. This model demonstrates that our previous understanding of the role of intracellular ATP in the control of adiponectin exocytosis needs to be revised to include an additional ATP-dependent step. Validation of the model by introduction of data of secreted adiponectin yielded a very close resemblance between the simulations and experimental results. Moreover, we could show that Ca-dependent adiponectin endocytosis contributes to the measured capacitance signal, and we were able to predict the contribution of endocytosis to the measured exocytotic rate under different experimental conditions. In conclusion, using mathematical modeling of published and newly generated data, we have obtained estimates of adiponectin exo- and endocytosis rates, and we have predicted adiponectin secretion. We believe that our model should have multiple applications in the study of metabolic processes and hormonal control thereof.

Exocytosis and Endocytosis: Yin-Yang Crosstalk for Sculpting a Dynamic Growing Pollen Tube Tip

“…The generation of theoretical models by mathematical analysis has been employed as a useful tool in biological studies to better understand the molecular basis of cells. More importantly, it helps to develop a testable hypothesis, apply the modeling on broader similar biological systems and stimulate new experiments ( Marco et al, 2007 ; Altschuler et al, 2008 ; Brannmark et al, 2017 ; Luo et al, 2017 ; Tian et al, 2019 ).…”

Adrenergic stimulation of adiponectin secretion in visceral mouse adipocytes is blunted in high-fat diet induced obesity

“…Visceral adipose tissue has been described to be more sensitive to adrenergic stimulation and an excess of visceral fat is associated with metabolic disease and increased mortality 4–6 . Own previous work has defined that adiponectin vesicles in adipocytes of subcutaneous origin (primary human and mouse adipocytes as well as cultured 3T3-L1 adipocytes) are rapidly released in response to an elevation of cytoplasmic cAMP and that intracellular Ca 2+ augments the secretion 23,45,46 . We have further demonstrated the catecholamine-triggered exocytosis of adiponectin vesicles and that catecholamine-stimulated adiponectin secretion is blunted in subcutaneous adipocytes from animals with diet-induced obesity.…”

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

“…Patch-clamp measurements of exocytosis and adiponectin secretion experiments are described in detail in (9). In short, 3T3-L1 cells were grown in plastic petri dishes (Nunc, Denmark) or 12-well plates (Sarstedt) and differentiation was induced by addition of a differentiation cocktail (5).…”

“…To deal with this high complexity, we have employed a systems biology approach combining experiments with mathematical modelling. We have previously developed a mathematical model for single-cell adiponectin exocytosis in 3T3-L1 adipocytes (9). In this work, changes in plasma membrane-capacitance is used to study exocytosis (10).…”

“…In this work, changes in plasma membrane-capacitance is used to study exocytosis (10). Such measurements were utilized to model how vesicle exo-and endocytosis are affected by different combinations of intracellular Ca 2+ , cAMP, and ATP concentrations (9). The concentrations of intracellular mediators were altered by inclusion of different concentrations in the patch pipette attached to the cell.…”