Mathematical modeling of white adipocyte exocytosis predicts adiponectin secretion and quantifies the rates of vesicle exo- and endocytosis
Mathematical modeling of white adipocyte exocytosis predicts adiponectin secretion and quantifies the rates of vesicle exo- and endocytosis
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DOI：
10.1074/jbc.m117.801225
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发表时间：
2017-12-08
影响因子：
4.8
通讯作者：
Olofsson, Charlotta S.
中科院分区：
文献类型：
--
作者：
Brannmark, Cecilia;Lovfors, William;Olofsson, Charlotta S.
脂联素是一种由白色脂肪细胞分泌的激素，参与多种代谢过程的调节。虽然脂联素的病理生理重要性已被彻底研究，其释放的控制机制只有部分了解。我们最近的研究表明，脂联素是通过含脂联素的囊泡的调节胞吐分泌的，脂联素的胞吐是由cAMP依赖性机制刺激的，并且Ca 2+和ATP增加cAMP触发的分泌。然而，关于脂联素释放的分子和细胞调节仍有许多有待发现。在这里，我们已经使用数学建模，以提取包含在我们以前获得的高分辨率膜片钳时间分辨电容记录的详细信息，以产生脂联素胞吐/分泌的第一个模型，结合所有的机械知识推导出的电生理实验系列。这个模型表明，我们以前的理解细胞内ATP在脂联素胞吐控制的作用需要修改，包括一个额外的ATP依赖的步骤。通过引入分泌型脂联素的数据对模型进行验证，模拟结果与实验结果非常相似。此外，我们可以表明，Ca 2+依赖的脂联素的内吞有助于测量的电容信号，我们能够预测的内吞的贡献，在不同的实验条件下测量的胞吐率。总之，使用数学建模的出版物和新产生的数据，我们已经获得了估计脂联素外吞和内吞率，我们预测脂联素分泌。我们相信，我们的模型应该有多种应用在代谢过程和激素控制的研究。
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 Ca2+ 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 Ca2+-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.