期刊
ISCIENCE
卷 23, 期 2, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.isci.2020.100855
关键词
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资金
- National Health and Medical Research Council (NHMRC) [GNT1061122, GNT1086850]
- Judith and David Coffey Fund
- Cancer Institute NSW [CDF181241]
- NHMRC Early Career Fellowship [APP1072440]
- Australian Diabetes Society Skip Martin Early Career Fellowship
- Diabetes Australia Research Project grant
- Creation of Fundamental Technologies for Understanding and Control of Biosystem Dynamics, CREST from the Japan Science and Technology Agency (JST) [JPMJCR12W3]
- Japan Society for the Promotion of Science (JSPS) KAKENHI Grant [17H06300]
- AMED-CREST from AMED
- AMED-CREST from Yamagata prefectural government
- City of Tsuruoka
- Sydney Informatics Hub - University of Sydney
- JSPS (KAKENHI grant) [JP15H05582, JP18H05431]
- PRESTO from the JST [JPMJPR1538]
- Grants-in-Aid for Scientific Research [17H06300] Funding Source: KAKEN
Cellular metabolism is dynamic, but quantifying non-steady metabolic fluxes by stable isotope tracers presents unique computational challenges. Here, we developed an efficient C-13-tracer dynamic metabolic flux analysis (13C-DMFA) framework for modeling central carbon fluxes that vary over time. We used 6-splines to generalize the flux parameterization system and to improve the stability of the optimization algorithm. As proof of concept, we investigated how 3T3-L1 cultured adipocytes acutely metabolize glucose in response to insulin. Insulin rapidly stimulates glucose uptake, but intracellular pathways responded with differing speeds and magnitudes. Fluxes in lower glycolysis increased faster than those in upper glycolysis. Glycolysis fluxes rose disproportionally larger and faster than the tricarboxylic acid cycle, with lactate a primary glucose end product. The uncovered array of flux dynamics suggests that glucose catabolism is additionally regulated beyond uptake to help shunt glucose into appropriate pathways. This work demonstrates the value of using dynamic intracellular fluxes to understand metabolic function and pathway regulation.
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