Mathematical modeling of white adipocyte exocytosis predicts adiponectin secretion and quantifies the rates of vesicle exo- and endocytosis
Artikel i vetenskaplig tidskrift, 2017

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.

exocytosis

electrophysiology

mathematical modeling

endocytosis

adiponectin

adipokine

adipocyte

Författare

Cecilia Brännmark

Sahlgrenska akademin

William Lövfors

Sahlgrenska akademin

Linköpings universitet

Ali M. Komai

Sahlgrenska akademin

Tom Axelsson

Linköpings universitet

Mickaël F. El Hachmane

Sahlgrenska akademin

Musovic Saliha

Sahlgrenska akademin

Alexandra Paul

Chalmers, Biologi och bioteknik, Kemisk biologi

Elin Nyman

AstraZeneca AB

Charlotta S Olofsson

Göteborgs universitet

Sahlgrenska akademin

Journal of Biological Chemistry

0021-9258 (ISSN) 1083-351X (eISSN)

Vol. 292 20032-20043

Ämneskategorier

Cellbiologi

Cell- och molekylärbiologi

Fysiologi

Systemvetenskap

Matematisk analys

Styrkeområden

Livsvetenskaper och teknik

DOI

10.1074/jbc.M117.801225